Patients with untreated brain metastases, spinal cord compression, or leptomeningeal carcinomatosis should be excluded from this clinical trial; patients whose brain metastases have been treated may participate provided they show radiographic stability (defined as 2 brain images, both of which are obtained after treatment to the brain metastases; these imaging scans should both be obtained at least four weeks apart and show no evidence of intracranial progression); in addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on a steroid dose of =< 10 mg/day of prednisone or its equivalent (and anti-convulsants) for at least 14 days prior to the start of treatment No evidence of distant metastases Participants with known brain metastases or leptomeningeal metastases must be excluded unless they qualify for enrollment as described below because of poor prognosis and concerns regarding progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; participants with brain metastases are permitted if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks or more after treatment is complete and within 4 weeks prior to the first dose of nivolumab administration Known uncontrolled central nervous system (CNS) metastases and/or carcinomatous meningitis. Note: Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are clinically stable off steroids for at least 7 days prior to study treatment. Carcinomatous meningitis precludes a patient from study participation regardless of clinical stability. Inclusion Criteria\n\n Histologically confirmed HER2+ breast carcinoma, with HER2+ defined by in situ\n hybridization (ISH) or fluorescence in situ hybridization (FISH) methodology\n\n Received previous treatment with trastuzumab, pertuzumab, and T-DM1\n\n Progression of unresectable locally advanced or metastatic breast cancer after last\n systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy\n\n Have measurable or non-measurable disease assessable by RECIST 1.1\n\n At least 18 years of age at time of consent\n\n Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1\n\n Adequate hepatic and renal function\n\n Left ventricular ejection fraction (LVEF) ? 50%\n\n CNS Inclusion - Based on screening brain magnetic resonance imaging (MRI), patients must\n have one of the following:\n\n - No evidence of brain metastases\n\n - Untreated brain metastases not needing immediate local therapy\n\n - Previously treated brain metastases not needing immediate local therapy\n\n 1. Brain metastases previously treated with local therapy may either be stable since\n treatment or may have progressed since prior local CNS therapy\n\n 2. Patients treated with CNS local therapy for newly identified lesions found on\n contrast brain MRI performed during screening for this study may be eligible to\n enroll if the following criteria are met:\n\n i. Time since whole brain radiation therapy (WBRT) is ? 21 days prior to first dose of\n study treatment, time since stereotactic radiosurgery (SRS) is ? 7 days prior to first\n dose of study treatment, or time since surgical resection is ? 28 days.\n\n ii. Other sites of evaluable disease are present\n\n c. Relevant records of any CNS treatment must be available to allow for classification of\n target and non-target lesions\n\n Exclusion Criteria\n\n Previously been treated with:\n\n 1. lapatinib within 12 months of starting study treatment (except in cases where\n lapatinib was given for ? 21 days and was discontinued for reasons other than disease\n progression or toxicity)\n\n 2. neratinib, afatinib, or other investigational HER2/epidermal growth factor receptor\n (EGFR) tyrosine kinase inhibitor (TKI) at any time previously\n\n 3. previously been treated with capecitabine for metastatic disease except in cases where\n capecitabine was given for < 21 days and was discontinued for reasons other than\n disease progression or toxicity. Patients who have received capecitabine for adjuvant\n or neoadjuvant treatment at least 12 months prior to starting study treatment are\n eligible.\n\n Clinically significant cardiopulmonary disease\n\n Carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease\n\n Positive for human immunodeficiency virus (HIV)\n\n Unable for any reason to undergo MRI of the brain\n\n CNS Exclusion - Based on screening brain MRI, patients must not have any of the following:\n\n Any untreated brain lesions > 2.0 cm in size, unless discussed with medical monitor\n\n Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a\n total daily dose of > 2 mg of dexamethasone (or equivalent)\n\n Any brain lesion thought to require immediate local therapy. Patients who undergo local\n treatment for such lesions identified by screening contrast brain MRI may still be eligible\n for the study based on criteria described under CNS inclusion criteria\n\n Known or concurrent leptomeningeal disease (LMD)\n\n Poorly controlled seizures Known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to registration for protocol therapy and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least seven days prior to registration for protocol therapy Have known symptomatic brain metastases requiring steroids. Subjects with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and have radiographically stable disease for at least 3 months prior to study entry. Note: up to 10 mg per day of prednisone equivalent will be allowed. Patients with any known brain or leptomeningeal metastases are excluded, even if treated. No evidence of distant metastases Patients with known brain active and untreated metastases should be excluded from this clinical trial Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not requiring steroids for at least 7 days prior to trial treatment Patients with untreated brain metastases are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; a scan to confirm the absence of brain metastases is not required; the patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment; patients with spinal cord compression are also excluded unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days Patients with brain metastases or primary brain tumors must have completed treatment, surgery or radiation therapy >= 4 weeks prior to start of treatment Patients with brain metastases or primary brain tumors must have completed treatment, surgery or radiation therapy >= 28 days prior to registration and have stable disease at time of registration; metastatic brain parenchymal disease must have been treated and patient must be off steroids for 7 days prior to registration; patients must have a CT or MRI scan of the brain to evaluate for central nervous system (CNS) disease within 42 days prior to registration Patients with known brain metastases must either meet the additional criteria and enroll as part of the Progressive Brain Metastases Cohort, or have clinically controlled neurologic symptoms, defined as surgical excision and/or radiation therapy followed by 14 days of stable neurologic function prior to registration; patients with previously incidentally discovered or asymptomatic brain metastasis(es) must receive surgical excision and/or radiation therapy prior to registration; patients with progressive brain metastases following prior treatment are not eligible for the Standard Cohort, but may be considered for the Progressive Brain Metastases Cohort Progressive Brain Metastases Cohort\r\n* S1416 is one study with two cohorts; patients who have progressive brain metastases after surgical excision and/or intracranial radiation will be in the Progressive Brain Metastases Cohort and will require a baseline magnetic resonance imaging (MRI); patients with previously treated brain metastases, stable disease and stable neurologic function for 14 days prior to trial registration will be in the Standard Cohort and may obtain MRI of the brain at the physician’s discretion; randomization and treatment is the same for both cohorts\r\n* In addition to all of the previous eligibility criteria, patients with progressive brain metastases who do not satisfy the conditions to enroll in the standard cohort (neurologic stability for 14 days following surgery and/or radiation therapy) must also meet the following criteria to enroll as part of the brain metastases cohort:\r\n** Patients with progressive brain metastases must have a baseline brain MRI within 28 days prior to registration; brain metastases must be progressive and >= 10 mm in longest dimension on radiographic imaging AFTER prior intracranial radiation (IR) therapy (i.e., whol brain radiation therapy [WBRT], stereotactic radiosurgery [SRS], gamma knife [GK] or local equivalent); patients must not have evidence of diffuse leptomeningeal disease on brain MRI or by previously documented cerebrospinal fluid (CSF) cytology; discrete dural metastases are permitted; there must be no evidence of hemorrhage or impending herniation on baseline brain imaging; patients with contraindication to gadolinium-enhanced MRI imaging are not eligible\r\n** Patients must be on a stable or decreasing dose of steroids for >= 7 days prior to registration\r\n** If patient had an open brain biopsy, at least 28 days must have elapsed between biopsy and registration\r\n** Patients enrolling in the Progressive Brain Metastases Cohort can have received up to 3 prior lines of cytotoxic chemotherapy for metastatic disease; note that for enrollment in the standard cohort, patients must have had =< 1 prior cytotoxic regimen for metastatic disease Patients must not have brain metastases unless brain metastases have been treated and patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration Patients are ineligible if they have any currently active central nervous system (CNS) metastases; patients who have treated brain metastases (with either surgical resection or stereotactic radiosurgery [SRS]) could be eligible; patients must not have taken any steroids =< 10 days prior to randomization for the purpose of managing their brain metastases; patients with only whole brain irradiation for treatment of CNS metastases will be ineligible Patients are ineligible if they have any currently active CNS metastases; patients who have treated brain metastases (with either surgical resection or stereotactic radiosurgery [SRS]) could be eligible to proceed; patients crossing over from dabrafenib/trametinib to nivolumab (nivo)/ipilimumab (ipi) must not have taken any steroids =< 10 days prior to registration for the purpose of managing their brain metastases; patients with only whole brain irradiation for treatment of CNS metastases are ineligible Patients with brain metastases (either remote or current) or presence of carcinomatous meningitis are not eligible Patients with no known brain metastasis must have baseline brain imaging within 12 weeks prior to study registration not demonstrating brain metastases OR Patients with known brain metastases must have baseline brain imaging within 4 weeks prior to study registration and meet all of the following criteria:\r\n* Have completed treatment to all symptomatic brain metastases (with whole brain radiation or radiosurgery) >= 4 weeks prior to registration, or have undergone complete neurosurgical resection >= 3 months prior to registration\r\n* Be clinically stable from brain metastases at time of screening, if no treatment was administered\r\n* Known leptomeningeal disease is not allowed Patients must have had no prior radiation therapy with the exception of CNS irradiation of brain metastases; (this exception only applies to SR1 patients; any patients over age 11 with distant metastases to brain [stage IV disease] would be considered poor risk and therefore not eligible for this trial) Patients who have a history of brain metastasis are eligible for the study provided that all the following criteria are met:\r\n* Brain metastases which have been treated\r\n* No evidence of disease progression for >= 3 months before the first dose of study drug\r\n* No hemorrhage after treatment\r\n* Off-treatment with dexamethasone for 4 weeks before administration of the first dose of TAK-228\r\n* No ongoing requirement for dexamethasone or anti-epileptic drugs Participants may not have clinically symptomatic brain metastases or leptomeningeal disease; patients may be on a stable dose of corticosteroids to control brain metastases if they have been on a stable dose for two weeks (14 days) prior to study treatment and are clinically asymptomatic No current symptomatic, untreated, or uncontrolled brain metastases present Prior radiotherapy for patients with brain metastases prior to enrollment is acceptable. Patients with brain metastases are eligible if these lesions have been previously treated and the patients have no clinical or radiographic evidence of progression within 30 days prior to enrollment. Clinical or radiologic evidence of new, untreated, and/or progressive brain metastases prior to registration after induction systemic therapy. Patients must not have known brain metastases unless brain metastases have been treated and patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 14 days prior to registration Brain metastases At least 1 measurable unirradiated parenchymal brain metastasis within 21 days prior to study entry; patients who are to undergo SRS must have no more than 10 brain metastases; there is no limit on number of brain metastases for WBRT; the minimum size as measured on T1-weighted gadolinium-enhanced MRI must be as follows according to the number of brain metastases:\r\n* For a single solitary lesion the size must be >= 10 mm\r\n* For 2 or more lesions, the size of at least 2 of the lesions must be >= 5 mm\r\n* Patients may also have the following provided the size requirements above are met:\r\n** Progressive parenchymal brain metastasis following stereotactic radiosurgery for 1-3 brain metastases, with at least 1 new measurable brain lesion\r\n** Progressive parenchymal brain metastasis following surgical resection of 1-3 brain metastases, with at least 1 measurable brain lesion Patients with known brain metastases should be excluded from this clinical trial except as those described below Known symptomatic brain metastases Participants with known brain metastases will be eligible if they have completed the primary brain therapy (such as whole brain radiotherapy, stereotactic radiosurgery or complete surgical resection) and if they have remained clinically stable, asymptomatic and off of steroids for at least 28 days before starting study treatment. Patient has symptomatic brain metastases (i.e., metastases that are accompanied by neurological symptoms or that require treatment with corticosteroids) Primary brain cancers or active CNS metastases should be excluded from this clinical trial Participants with symptomatic uncontrolled brain metastases; baseline brain imaging by CT or MRI is required for all patients; participants with brain metastases that have been treated with prior radiation therapy and are stable on a subsequent scan are allowed; participants with untreated possible brain metastases that are new at the time of screening and are < 1 cm and asymptomatic are allowed; the participant can receive corticosteroids as long as these were started and at a stable dose at least 28 days prior to treatment Participants with known untreated brain metastases are excluded from this clinical trial No active brain metastases Patients with untreated brain metastases. Patients with treated brain metastases who are off corticosteroids for at least two weeks and who demonstrate control of brain metastases with follow-up imaging 4 or more weeks after initial therapy are eligible. Patients with brain metastases treated with whole brain radiation that have been stable for 2 months are eligible; patients with brain metastases treated with gamma knife or surgery are allowed to participate after 3 weeks have elapsed since their procedure; demonstration of brain stability by an imaging study after the procedure is required for gamma knife or central nervous system (CNS) surgery patients; subjects are excluded if they have leptomeningeal or metastases causing spinal cord compression that are symptomatic or untreated or not stable for >= 3 months (must be documented by imaging) or requiring corticosteroids; subjects on a stable dose of corticosteroids > 1 month or who have been off of corticosteroids for at least 1 week can be enrolled with approval of the medical monitor Brain metastases requiring steroids Brain Tumors Known brain metastases (unless previously treated and well controlled for a period of at least 3 months). Symptomatic or unstable brain metastases; (Note: Asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days prior to randomization are eligible to participate in the study) Participants with known brain metastases Distant metastases Participants with known brain metastases should be excluded from this clinical trial Participants with known metastases Known symptomatic brain metastases (NOTE: patients with treated epidural disease are allowed) 16. Symptomatic or untreated central nervous system metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation, and/or corticosteroids. Subjects with previously treated brain metastases may participate provided they are clinically stable for at least 8 weeks prior to study entry, have no evidence of new or enlarging metastases, and are off steroids; Known central nervous system, meningeal, or epidural disease. However, subjects with known brain metastases are allowed if the brain metastases are stable for ?4 weeks before the first dose of study treatment. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging (using the identical imaging modality for each assessment, either MRI or CT scan) for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. Has known central nervous system (CNS) metastases. Patients with previously treated brain metastases may participate provided they are: Have no evidence of new or enlarging brain metastases Known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Participants with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study; any signs (e.g. radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment; participants with leptomeningeal disease should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events Known uncontrolled central nervous system (CNS) metastases and/or carcinomatous meningitis. Note: Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are clinically stable off steroids for at least 7 days prior to study treatment. Carcinomatous meningitis precludes a patient from study participation regardless of clinical stability. Known active central nervous system metastases, brain metastases, or carcinomatous meningitis Subjects with treated brain metastases are eligible provided they meet the following criteria: Untreated or symptomatic brain metastases and leptomeningeal disease Participants with known brain metastases should be excluded; screening for brain metastases with head imaging is not required Uncontrolled brain metastases Leptomeningeal metastases CNS malignancy, the known presence of untreated or symptomatic CNS metastases. Subjects with treated brain metastasis must be stable and off steroids and anti-convulsants for at least 1 month prior to the start of study treatment. Subjects with suspected brain metastases at Screening should have a CT/MRI of the brain prior to study entry. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Known untreated brain or leptomeningeal metastasis\r\n* Patients with brain metastases are eligible if metastases have been adequately treated and neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least two weeks prior to C1D1 and meet requirements related to steroids Females who are pregnant or breastfeeding. ? Patients who have active or stable brain metastases or who have a history of brain metastases. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks and any neurologic symptoms have returned to baseline), they have no evidence of new or enlarging brain metastases (confirmed by imaging within 28 days [d] of the first dose of trial treatment), and they are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Participants with symptomatic brain metastases that require active treatment are excluded Known uncontrolled brain, leptomeningeal or epidural metastases (unless treated and well controlled for at least 4 weeks prior to Cycle 1 Day 1). Controlled brain metastases that require continuous high dose corticosteroid use within 4 weeks of Cycle 1 Day 1. Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms; participants with previously diagnosed brain metastases are eligible if they have completed treatment at least one month prior to trial therapy initiation, are neurologically stable with an absence of new neurological symptoms for at least 4 weeks prior to study entry, and have recovered from effects of radiotherapy or surgery; any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 2 weeks before the first study drug; treatment for brain metastases may include whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating physician Subjects with brain metastases Any current brain or subdural metastases Participants with CNS metastases are not eligible, unless they have completed local therapy (eg, whole brain radiation therapy [WBRT], surgery or radiosurgery) and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs (eg, radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment Patients with evidence of active brain metastases, or active leptomeningeal disease are ineligible; patients with a history of brain metastases must have completed treatment (i.e. surgery or radiation) prior to enrollment EXCLUSION CRITERIA FOR SECOND-LINE THERAPY: Known or suspected brain or central nervous system metastases, irrespective of prior treatment EXCLUSION CRITERIA FOR THIRD-LINE THERAPY: Known or suspected brain or central nervous system metastases, irrespective of prior treatment Active brain metastases Some types of brain metastases Patients may not have diagnosed brain metastases Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 28 days prior to registration and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability COHORT A: Previously untreated asymptomatic brain metastases COHORT D: 1-4 brain metastases (where stereotactic radiosurgery would be indicated) Will need immediate local surgery or radiation for their brain metastases Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; note: patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are off steroids or on a stable or decreasing dose of =< 10 mg daily prednisone (or equivalent); this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases SAFETY RUN-IN: Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment RANDOMIZED PHASE II CLINICAL TRIAL: Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Brain metastases (brain imaging is not required) For Group A: Subjects with a history of brain metastases are ineligible. This includes previously treated brain metastases. For Group B (subjects with AML): Active symptomatic CNS involvement of AML. Subjects with previously treated leptomeningeal disease that has been effectively treated are eligible. Symptomatic brain metastases or any leptomeningeal metastasis that is symptomatic and/or requires treatment. Subjects with brain metastases are eligible if these have been locally treated (surgery, radiotherapy). There must also be no requirement for immunosuppressive doses of systemic corticosteroids (>10 mg/day prednisone equivalent) for at least 2 weeks before the first dose of study treatment Participants with known brain metastases should be excluded from this clinical trial Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Participants with untreated brain metastases. Participants with treated metastases that are clinically stable and asymptomatic for at least 2 weeks and who are off or receiving low-dose corticosteroid treatment (=<10 mg prednisone or equivalent) for at least 2 weeks prior to study treatment are eligible Untreated or clinically active melanoma brain metastases. Subjects with ? 3 brain metastases and each ? 1 cm size that were treated with either surgical resection and/or radiation therapy are eligible for study participation provided (a) there is no evidence of progressive central nervous system (CNS) disease on brain imaging at least 30 days after definitive treatment and (b) the subject is not taking prednisone at >10 mg or equivalent daily. Subjects with > 1 cm or > 3 in number treated brain metastases are eligible for study participation provided (a) there is no evidence of progressive CNS disease on brain imaging at least 90 days after treatment with surgery and/or radiation therapy and (b) if the subject is not taking prednisone at >10 mg or equivalent daily. Patients with uncontrolled brain metastases. Uncontrolled brain metastases Leptomeningeal metastases Brain metastases. Patients with known brain metastases should be excluded from this clinical trial; however, patients with previously treated and stable brain metastases are eligible as long as they are no longer requiring steroids, completed radiation therapy more than 2 weeks prior to the first dose of study regimen and have no seizures or worsening neurologic symptoms Partial brain radiotherapy (i.e. =< 40% of total brain volume) within the last 2 weeks Whole brain radiotherapy within the last 6 months or partial brain radiotherapy exceeding > 40% of total brain volume within the last 6 months No history or evidence by CT scan or MRI, of brain metastases or leptomeningeal disease. Known brain metastases If there is a known history of brain metastases, either treated with radiation therapy or untreated, the metastatic disease must be stable in the judgment of the Principal Investigator and must not require ongoing treatment with corticosteroids or anticonvulsants. Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases; asymptomatic or treated brain metastases are acceptable Brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery and stable for at least 3 months before planned first dose of study drug Has clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with steroids may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 4 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment (2 weeks for stereotactic radiotherapy). Patients with central nervous system metastases are excluded; Note: subjects with previously treated (radiotherapy or surgery) brain metastasis that have been stable without steroid treatment for at least 3 months following prior treatment may be enrolled History of central nervous system (CNS) disease; Note: patients with brain metastases will be eligible if treated appropriately and if they remain clinically stable neurologically; for asymptomatic brain metastases, appropriate clinical treatment may include observation with serial imaging Patients with previously untreated brain metastases (including parenchymal, meningeal or dural-based central nervous system [CNS] lesions) are excluded; however, patients with previously treated (surgery, radiation or both), clinically inactive brain metastases, who have not received corticosteroid therapy within three weeks of starting protocol therapy, are eligible Uncontrolled brain or leptomeningeal metastases from plexiform neurofibromas, malignant peripheral nerve sheath tumors, or other cancers (other than proven or probable low grade astrocytomas), including patients who continue to require glucocorticoids for control of symptoms related to brain or leptomeningeal metastases Patients with metastases Patients with known brain metastases or carcinomatous meningitis are excluded from this clinical trial, with the exception of patients whose brain metastatic disease status has remained stable for >= 1 month after treatment of the brain metastases; patients on anti-seizure medications may be enrolled at the discretion of the principal investigator Participants with known brain metastases or carcinomatous meningitis are excluded from this clinical trial, with the exception of patients with brain metastatic disease that has previously been treated and remained stable on MRI >= 2 months prior to enrollment, without steroids or anti-epileptic medications. These patients may be enrolled at the discretion of the principal investigator. Patients with symptomatic brain metastases are excluded. Patients with asymptomatic and treated CNS metastases may participate in this trial. The patient must have completed any prior treatment for CNS metastases > 28 days prior to study entry including radiotherapy or surgery. Steroids for the treatment of brain metastasis are not permitted, and patients must be stable off steroid treatment for 4 weeks prior to enrollment. Participants must have a diagnosis of brain metastases for which SRS is indicated, as determined by a radiation oncologist Participants with known untreated brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Participants with a history of brain metastases that have been treated, are no longer taking corticosteroids, and have been stable on imaging for >= 4 weeks following the last date of treatment are permitted Participants who have undergone prior radiation for brain metastases; patients who have undergone resection of one or more brain metastases but who have not yet started adjuvant radiotherapy are eligible for the study Participants who have received prophylactic cranial radiation for prevention of brain metastases Participants with > 6 definitive lesions consistent with brain metastases Active brain metastases or leptomeningeal metastases Known active central nervous system (CNS) metastases and/or carcinomatous meningitis; patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for management of brain metastases for at least 7 days prior to study treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Participant has untreated brain or meningeal metastases. Subject with known brain metastases should be excluded from this clinical trial; however, baseline brain imaging is not required prior to enrollment in the study if patients are asymptomatic Brain metastases that: Or have required any type of major treatment, e.g., whole brain radiation treatment, adjuvant chemotherapy, gamma knife, to control symptoms from brain metastases within 30 days of the first study treatment. Known active central nervous system involvement and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; patients with previously treated brain metastases may participate provided:\r\n* No current brain metastasis lesion greater than 2 cm. Patients with prior metastasis lesions greater than 2 cm that have been removed by surgical and/or radiotherapy may be enrolled if the lesion has been stable since surgery or radiotherapy.\r\n* No new or progressing brain metastasis of any size.\r\n* No stereotactic radiation or craniotomy within 4 weeks of cycle 1 day 1.\r\n* They are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment.\r\n* No clinically significant symptoms secondary to brain metastases. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. Patients are excluded if they have active brain metastases or leptomeningeal metastases; subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for [lowest minimum is 4 weeks or more] after treatment is complete and within 28 days prior to the first dose of nivolumab administration; there must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration Known symptomatic brain metastases requiring ?10 mg/day of prednisolone (or its equivalent). Patients who have known active central nervous system (CNS) metastases and/or carcinomatous meningitis are not eligible \r\n* NOTE: Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to registration; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Known intracranial metastases ENROLLMENT TO THE DOSE ESCALATION, EXPANSION AND PART II: Participants with known untreated brain metastases are excluded; patients with a history of brain metastases are permitted to enroll if they have been treated, are no longer taking corticosteroids, and have been stable for a minimum of one month on imaging; exceptions for participants with asymptomatic sub-centimeter metastases that, in the opinion of the treating investigator, do not require intervention may be possible following discussion and agreement with the overall principal investigator Patients with known symptomatic brain metastases requiring steroids in part 1 or 2 For part 1 (dose escalation) only, patients with previously diagnosed brain metastases are eligible as long as they do not require central nervous system (CNS)-directed therapy (including corticosteroids); if the patient has had radiation therapy or surgery, then they should have completed treatment and have discontinued corticosteroids for at least 2 weeks and must be neurologically stable; patients with brain metastases are excluded from part 2 (dose expansion) History or evidence of known brain metastases or carcinomatous meningitis; patients with known brain metastases must be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events Known brain metastases or carcinomatous meningitis. Exception: previously treated brain metastatic disease that remains stable on MRI ? 4 weeks prior to enrollment, without steroids or anti-epileptic medications Participants with known untreated brain metastases should be excluded from this clinical trial; participants with a history of brain metastases that have been treated, are no longer taking corticosteroids, and have been stable on imaging for >= 4 weeks following the last date of treatment are permitted Subjects with previously treated brain metastases may participate provided they are not using escalating steroids for brain metastases at the time of trial consent and study drug initiation, and there remains a measurable lesion in the CNS Brain metastases with risk of mass effect that would contraindicate lumbar puncture Those with known brain metastases should be excluded from this clinical trial Participant has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment), have no evidence of new or enlarging brain metastases, and are not using steroids for the purposes of treating brain metastasis induced edema for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability, because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms; participants with previously diagnosed brain metastases are eligible if they have completed treatment at least 2 weeks prior to trial therapy initiation, are neurologically stable, and have recovered from the acute effects of radiotherapy or surgery; any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 2 weeks before the initiating protocol therapy; treatment for brain metastases may include surgery, whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating physician Subjects with known symptomatic brain metastases or leptomeningeal metastases Participants who have undergone prior radiation for brain metastases; patients who have undergone resection of one or more brain metastases but who have not yet started adjuvant radiotherapy are eligible for the study Patients with known brain metastases or carcinomatous meningitis are excluded from this clinical trial, with the exception of patients with brain metastatic disease that has previously been treated and remained stable on MRI >= 2 months prior to enrollment, without steroids or anti-epileptic medications; these patients may be enrolled at the discretion of the principal investigator Symptomatic brain metastases; stable and treated central nervous system (CNS) disease allowed; patients with treated, asymptomatic brain metastases are eligible if there has been no change in brain disease status for at least two (2) weeks prior to initiating study treatment; anticonvulsant therapy will be allowed if patient is on a stable or decreasing dose of anticonvulsant treatment for at least two (2) weeks prior to initiating study treatment Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms; participants with previously diagnosed brain metastases are eligible if they have:\r\n* Completed treatment (whole brain radiotherapy, radiosurgery, or a combination) at least 3 months prior to trial therapy initiation,\r\n* Are neurologically stable, and\r\n* Have recovered from effects of radiotherapy or surgery\r\n* Any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 2 weeks before prior to registration Patients with known brain metastases should be excluded from this clinical trial Patients with known brain metastases or carcinomatous meningitis are excluded from this clinical trial, with the exception of patients whose brain metastatic disease status has remained stable for >= 1 month after treatment of the brain metastases; patients on anti-seizure medications or steroid therapy may be enrolled at the discretion of the principal investigator Patients with brain metastases unless they meet the criteria Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms; patients with a history of treated central nervous system (CNS) metastases are eligible; treated brain metastases are defined as those having no evidence of progression for >= 1 month after treatment, or hemorrhage for >= 2 weeks after treatment and no ongoing requirement for corticosteroids, as ascertained by clinical examination and brain imaging (magnetic resonance imaging or CT scan) during the screening period; any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 2 weeks before the first study drug; treatment for brain metastases may include whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating physician; patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 1 month before day 1 of study treatment will be excluded Known brain metastases Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis. NOTE: Subjects with previously treated brain metastases may participate provided have no evidence of new or enlarging brain metastases, and Leptomeningeal metastases Recurrent brain metastases Patients with unstable brain metastases should be excluded; however, patients with known brain metastases may participate in this clinical trial if they are clinically stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are on a stable or decreasing dose of steroids for at least 14 days prior to trial treatment Active or untreated brain metastases The participant has active brain metastases or epidural disease; participants with brain metastases previously treated with whole brain radiation or radiosurgery or participants with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 4 weeks before starting study treatment are eligible; participants with treated brain metastasis should not take enzyme-inducing anticonvulsive therapies (EIACDs) within 2 weeks of registration, though non-enzyme inducing anticonvulsive drugs such as levetiracetam are allowed; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain imaging with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans for participants with known brain metastases is required to confirm eligibility Patients with known brain metastases should be excluded from this clinical trial; a scan to confirm the absence of brain metastasis is not required Any known brain or leptomeningeal metastases are excluded, even if treated. Symptomatic or uncontrolled brain metastases Known malignant central nervous system (CNS) disease other than neurologically stable, treated brain metastases – defined as metastasis having no evidence of progression or hemorrhage for at least 2 weeks after treatment; must be off any systemic corticosteroids for the treatment of brain metastases for at least 14 days prior to enrollment; patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events Patients with known brain metastases Patients with brain metastases which are symptomatic may not be enrolled; those subjects with untreated brain metastases =< 1 cm may who are asymptomatic and for whom there are no plans for surgery, radiation or corticosteroid use may be considered eligible at the discretion of the principal investigator; subjects with brain metastases that have been treated and are stable for at least 1 month are eligible if they are asymptomatic and not receiving corticosteroids Patients with untreated symptomatic brain metastases may be eligible if symptoms do not require urgent surgery or radiation, and no steroids are necessary Uncontrolled brain metastases (Stable brain metastases either treated or being treated with a stable dose of anticonvulsants, with no dose change within 28 days before enrollment, will be allowed.). Patient with untreated or inadequate controlled brain metastases. Brain metastases or lymphoma with CNS involvement previously treated by radiotherapy or other modality and stable for at least 3 months prior to screening without requirement of corticosteroids or anticonvulsants are permitted Participants with known untreated brain metastases should be excluded from this clinical trial; participants with a history of brain metastases that have been treated, are no longer taking corticosteroids, and have been stable on imaging for >= 4 weeks following the last date of treatment are permitted Untreated brain metastases (pts with treated brain mets who are off steroids and anticonvulsants and stable for at least 1 month at the time of Screening are eligible) Participants with known untreated brain metastases should be excluded from this clinical trial; participants with a history of brain metastases that have been treated, are no longer taking corticosteroids, and have been stable on imaging for at least one month following the end of treatment are permitted. Have symptomatic brain metastases or leptomeningeal disease Patients with 1-10 untreated brain metastases at time of initial brain metastases diagnosis (surgery to one of the brain lesions and/or biopsy of a lesion for diagnostic purposes and/or for standard of care purposes is acceptable) Largest brain metastases volume measures less than 14.15 cc^3 If they have brain metastases located in the brain stem (including midbrain, pons, or medulla) Participants with known brain metastases should be excluded Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients must be free of active brain metastases by contrast-enhanced computerized tomography (CT)/magnetic resonance imaging (MRI) scans within 4 weeks prior to starting the study drugs; if known to have prior brain metastases, must not have evidence of active (enlarging and/or symptomatic lesions) brain disease on two successive MRI evaluations at least 4 weeks apart (one of which is at least 4 weeks prior to starting the study drugs) Patients with brain metastases will be excluded if metastases have been symptomatic or actively treated within 4 weeks prior to enrollment Subjects with brain metastases are eligible Patients with known brain metastases will be eligible as long as they have completed radiation to the brain, and have been off of corticosteroid therapy for at least 7 days Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with leptomeningeal disease are not eligible but patients with brain metastases are eligible – these patients should commence treatment on study > 1 week after completion of gamma knife or whole brain radiotherapy or > 4 weeks after surgical resection of brain metastasis; patients should ideally be off steroids at the start of study treatment, however patients on steroid taper and a dose of no more than 2 mg/day of dexamethasone can begin study treatment; and steroids should be tapered off as quickly as clinically feasible; repeat brain magnetic resonance imaging (MRI) after radiation is not required for eligibility but is strongly recommended, to establish the pre-treatment baseline status of any brain metastases, necessary to accurately assess for response or progression; patients with untreated, asymptomatic brain metastasis not requiring steroids are also eligible, however, these patients need to be discussed with the study PI prior to being registered Patients with uncontrolled brain metastases. Existing brain metastases must have been previously treated and currently stable. Known brain metastases or leptomeningeal disease involvement. Glioblastoma lesions (primary or locally advanced) are eligible. Known brain metastases Patients must have between 1 to 5 new or recurrent lesions suspicious for metastatic RCC on diagnostic imaging\r\n* Each extracranial lesion must be =< 6 cm and amenable to SBRT or surgical excision\r\n* Patients must have 3 or fewer brain metastases, of size =< 4 cm\r\n** Brain metastases must be treated prior to enrollment in the study; the modality of treatment of brain metastases can include surgical resection, whole brain radiotherapy, stereotactic radiosurgery, or any combination of the above Patients with active brain or subdural metastases are not eligible, unless they have completed local (radiation) therapy and have discontinued the use of corticosteroids or have been on stable dose of corticosteroids for at least 4 weeks before starting study treatment; any symptoms attributed to brain metastases will be stable for at least 4 weeks before starting study treatment Subject has known active central nervous system (CNS) involvement; the subject has untreated brain or meningeal metastases; CT scans are not required to rule out brain or meningeal metastases unless there is a clinical suspicion of central nervous system disease; subjects with treated brain metastases that are radiographically or clinically stable for at least 4 weeks after therapy and have no evidence of cavitation or hemorrhage in the brain lesion(s) are eligible, providing that they are asymptomatic, and do not require corticosteroids (must have discontinued steroids at least 1 week prior to study drug administration) Patients with known untreated brain metastases; patients with known, treated brain metastases must be stable with no symptoms for four weeks after completion of that treatment, with image documentation required, and must either be off steroids or on a stable dose of steroids for at least two weeks prior to protocol enrollment; patients with known leptomeningeal metastases are excluded, even if adequately treated; patients without known brain metastases do not require radiologic imaging prior to enrollment The presence of known brain metastases Untreated or symptomatic brain metastases requiring corticosteroid therapy (no corticosteroid use for this purpose in the preceding 4 weeks) Patients with known brain metastases or carcinomatous meningitis are excluded from this clinical trial, with the exception of patients whose brain metastatic disease status has remained stable for >= 1 month after treatment of the brain metastases; patients should not be on anti-seizure medications; these patients may be enrolled at the discretion of the principal investigator Symptomatic metastatic brain or meningeal tumors, neuroblastoma (NB); if a patient does not have known or symptomatic central nervous system (CNS) metastases at screening, then brain imaging is not required for the purpose of this trial Patients who need whole brain radiation to control the brain metastases. Patients will not be eligible unless treated brain lesions are progressive or new brain lesions are observed since the post whole brain radiation therapy MRI. Brain metastases (symptomatic or nonsymptomatic) that have not been treated previously, are progressive, or require any type of therapy (e.g., radiation, surgery, or steroids) to control symptoms from brain metastases within 30 days prior to first study treatment dose Cobimetinib-Specific Exclusion Criteria Patients with known brain metastases will be excluded from this clinical trial Presence of leptomeningeal metastases Patients with known brain metastases will be excluded from this clinical trial No active intracranial metastases Presence of active brain metastases or epidural disease\r\n* Subjects with brain metastases are eligible if previously treated with whole brain radiation or radiosurgery, and do not require steroid treatment for at least 2 weeks before starting study treatment\r\n* Subjects with epidural disease are eligible if previously treated with radiation or surgery, are asymptomatic, and do not require steroid treatment for at least 2 weeks before starting study treatment Patients must have a brain magnetic resonance imaging (MRI) that is free of active metastases; metastases that have been treated with radiation or surgical resection, are stable for at least 4 weeks and do not require steroids are eligible Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible; patients with surgically resected brain metastases are eligible Patients with brain metastases may be eligible if all of the following are true:\r\n* The total number of brain metastases ever is less than or equal to 3.\r\n* The brain metastases have been completely removed by surgery or have been treated completely by stereotactic radiotherapy. Stereotactic radiotherapy, such as gamma knife, can be used up to 1 week prior to study entry. In the absence of concerning clinical findings, repeat scans are not required after stereotactic radiotherapy if the patient enrolls within 8 weeks of completing the stereotactic therapy.\r\n* There has been no evident growth of any brain metastasis since treatment.\r\n* No treated brain metastasis is greater than 2 cm in diameter at the time of protocol entry. Patients who have had brain metastases unless they meet the criteria. Patients with untreated known brain metastases, or treated brain metastases that are clinically unstable Known metastases in the brain or active epidural disease (NOTE: patients with treated epidural disease are allowed) Patient has known brain metastases, Patients with known brain metastases will only be eligible after their tumors have been treated with definitive resection and/or radiotherapy and they are neurologically stable for at least 1 month off steroids. Documented evidence of distant metastases Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible; patients with surgically resected brain metastases are eligible Active brain metastases or leptomeningeal disease. Previously treated brain metastases are allowed provided lesions are stable for at least 3 months as documented by head CT scan or magnetic resonance imaging (MRI) of the brain. Patients must be off steroids, but anti-convulsants are allowed. Patients with active brain metastases are not eligible; patients with brain metastases that have been treated and stable for > 30 days following treatment will be eligible Patients with active brain metastases or carcinomatous meningitis are excluded from this clinical trial; patients with treated brain metastases, whose brain metastatic disease has remained stable for >= 4 weeks without requiring steroid and anti-seizure medications are eligible to participate Patients with known active brain metastases or carcinomatous meningitis are excluded from this clinical trial; patients whose brain metastatic disease status has remained stable for >= 4 weeks following treatment of brain metastases are eligible to participate at the discretion of the principal investigator Subjects with known brain metastases should be excluded from this clinical trial Patients with known brain metastases should be excluded from this clinical trial Patients with known brain metastases Presence or history of brain metastases. History of brain metastases Patients can have concomitant brain metastases as long as they do not require active treatment or have been treated Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible; patients with surgically resected brain metastases are eligible Patients with known brain metastases unless treated with an appropriate modality with no evidence of progression/recurrence for > 3 months Patients with known brain metastases are not excluded from this clinical trial. Patients who received palliative radiation (for brain metastases) are eligible if they have been asymptomatic for at least 4 weeks without use of maintenance steroid therapy, and last received radiation at least 4 weeks prior to proposed start of therapy Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. All subjects with brain metastases, except those meeting the following criteria:\r\n* Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment\r\n* No history of intracranial or spinal cord hemorrhage\r\n* No evidence of interim central nervous system (CNS) disease progression\r\n* Metastasis to the midbrain, pons, and medulla\r\n* No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable.\r\n* Subjects must be either off steroids or on a stable or decreasing dose of =< 10 mg daily prednisone (or equivalent). Subjects with symptomatic brain metastases will be excluded from trial secondary to poor prognosis. However, subjects who have asymptomatic brain metastases, and those had treatment for their brain metastasis and whose brain disease is stable without steroid therapy for 2 weeks may be enrolled (replacement doses =< 10 mg of prednisone or equivalent per day are allowed) Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids; patients with treated brain metastases are eligible as long as they completed prior brain radiation therapy more than 14 days prior to first dose of study therapy, are not experiencing seizures and are not receiving steroids for symptomatic brain metastases (for at least 7 days prior to first dose of study treatment) Subjects with untreated or uncontrolled brain metastases. Patients with asymptomatic brain metastases or previously treated brain metastases that are stable (i.e. not requiring corticosteroids) at the time of study start will be eligible Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Has known brain metastases or spinal cord compression unless the patient is stable (asymptomatic; no evidence of new or emerging brain metastases; and stable and off steroids for at least 14 days prior to start of study treatment); following radiotherapy and/or surgery of the brain metastases patients must wait 4 weeks following the intervention and before initiating study treatment with imaging to confirm stability Symptomatic or clinically active brain metastases Prior whole brain radiotherapy. Patients with untreated or uncontrolled brain metastases or evidence of leptomeningeal disease. Patients with asymptomatic brain metastases or previously treated brain metastases that are stable (i.e. not requiring corticosteroids) at the time of study start will be eligible History of prior brain metastases Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have a magnetic resonance imaging (MRI) (preferred) or CT each preferably with IV contrast of the brain prior to study entry or brain metastases or spinal cord compression unless the patient is stable (asymptomatic; no evidence of new or emerging brain metastases; and stable and off steroids and anti-convulsants for at least 14-28 days prior to start of study treatment). Following radiotherapy and/or surgery of the brain metastases patients must wait 4 weeks following the intervention to confirm stability. Patients with 3 or fewer brain metastases that are less than 1 centimeter (cm) in diameter and asymptomatic are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for one month after treatment for the patient to be eligible; patients with surgically resected brain metastases are eligible Participants must not have active brain metastases or leptomeningeal metastases Known central nervous system (CNS) disease, except for treated brain metastasis: Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT]) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; gamma knife, linear accelerator [LINAC], or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 will be excluded Patients who have metastases to the brain. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability The patient has active brain metastases Known brain metastases; patients with known brain metastases must be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events History of known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to initiation of lymphodepletion. Known brain or leptomeningeal metastases History of, or current brain metastases Untreated symptomatic brain metastases (treated brain metastases are allowed provided > 14 days have elapsed from completion of radiotherapy and patient is neurologically stable as assessed by treating physician) Participants must not have known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 2 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients who have a history of brain metastasis are eligible for the study provided that all the following criteria are met: a) Brain metastases which have been treated b) No evidence of disease progression for >= 3 months before the first dose of study drug. c) No hemorrhage after treatment d) Off-treatment with dexamethasone for 4 weeks before administration of the first dose of TAK-228 e) No ongoing requirement for dexamethasone or anti-epileptic drugs. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 30 days prior to trial treatment; patients who had oligometastatic disease treated with stereotactic radiation or gamma knife therapy may receive treatment 14 days after therapy as long as they are not requiring steroids; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with known brain metastases or leptomeningeal carcinomatosis will be excluded from this clinical trial. Patients with suspected brain metastases at screening should have an magnetic resonance imaging (MRI) (preferred) or computed tomography (CT) each preferably with intravenous (IV) contrast of the brain prior to study entry. Uncontrolled central nervous system (CNS) metastases, including leptomeningeal metastases, are not allowed; subjects with previously treated brain metastases will be allowed if the brain metastases have been stable without steroid treatment for at least 2 weeks (radiotherapy or surgery) Known brain metastases who are clinically unstable Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability For cohorts 1-3, patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible; patients with surgically resected brain metastases are eligible Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 2 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Has known active central nervous system (CNS) metastases and/or lymphomatous meningitis; subjects with previously treated brain metastases or lymphomatous meningitis may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Has clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms (participants with treated brain metastases that are no longer symptomatic and who require no treatment with steroids may be included in the study if they have recovered from the acute toxic effect of radiotherapy) Radiographically confirmed solid tumor brain metastases Patients with more than 4 brain metastases on MRI brain or CT head Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Subject has known symptomatic brain metastases or leptomeningeal involvement as assessed by CT scan or MRI. Subjects with stable asymptomatic brain metastases or leptomeningeal disease are eligible provided that they have not required new treatments for this disease in a 28 day period before the first dose of study drug, and anticonvulsants and steroids have not been administered for a period of 2 weeks prior to the first dose of study drug. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiological stable (i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to the first dose of trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. COHORT 1: HORMONE RECEPTOR POSITIVE BREAST CANCER: Patients with symptomatic brain metastases or leptomeningeal involvement; patients with asymptomatic or brain metastases that have been treated with radiation at least 4 weeks prior to first dose of study treatment are allowed COHORT 2: TRIPLE NEGATIVE BREAST CANCER: Patients with symptomatic brain metastases or leptomeningeal involvement; patients with asymptomatic or brain metastases that have been treated with radiation at least 4 weeks prior to first dose of study treatment are allowed COHORT 3: ENDOMETRIAL CANCER: Patients with symptomatic brain metastases or leptomeningeal involvement; patients with asymptomatic or brain metastases that have been treated with radiation at least 4 weeks prior to first dose of study treatment are allowed Subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of disease for 4 weeks after treatment is complete and within 28 days prior to the first dose of nivolumab. Subjects with asymptomatic brain metastases are eligible, though if treated with radiation or surgery the above criteria apply regarding a 28-day washout and MRI to assess for progression after 4 weeks. Subjects with primary brain cancers or active CNS metastases should be excluded from this clinical trial Patients with untreated brain metastases, spinal cord compression, or evidence of symptomatic brain metastases or leptomeningeal disease as noted on computed tomography (CT) or magnetic resonance imaging (MRI) scans are excluded from this clinical trial; while screening brain MRI is not required, it should be performed if clinically indicated at the discretion of the treating investigator; should patient found to have brain metastasis, treatment of brain metastasis must precede the participation in this study For patients with known and treated brain metastases is allowed in this study if they fulfill ALL of the following criteria:\r\n* The lesions have remained radiologically stable for at least six weeks after completion of brain irradiation or stereotactic brain radiosurgery, and must remain stable at the time of study entry\r\n* There is no mass effect present radiologically and no steroids requirement for symptom control for more than 4 weeks Patient has symptomatic brain or CNS metastases Patients with known brain metastases should be excluded from this clinical trial Patients with known symptomatic brain metastases requiring steroids Patients must have a history of brain metastases that are non-progressing. Known symptomatic uncontrolled brain or leptomeningeal metastases (Day 1) Patients with a prior history of brain metastases are eligible provided:\r\n* The brain metastases have been treated\r\n* The patient is asymptomatic from the brain metastases\r\n* Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration\r\n* The brain metastases are stable on pre-registration imaging Participants with symptomatic known brain metastases < 4 weeks from radiation treatment should be excluded from this clinical trial Documented evidence of distant metastases Active central nervous system metastases and/or carcinomatous meningitis (stable treated brain metastases not requiring steroids > 4 weeks allowed) Patients with evidence of symptomatic brain metastases. Patients with treated (surgically excised or irradiated) and stable brain metastases are eligible assuming the patient has adequately recovered from treatment, the treatment was at least 28 days prior to initiation of study drug, and baseline brain computed tomography (CT) with contrast, or magnetic resonance imaging (MRI) within 14 days of initiation of study drug, is negative for new or worsening brain metastases Patients who have known leptomeningeal metastases or untreated or symptomatic brain metastases; treated, asymptomatic brain metastasis can be included History of brain metastases or who currently have treated or untreated brain metastases Metastases in the brain Primary brain or spine tumor are eligible, including tumors with metastases, multiple lesions ARM I INCLUSION CRITERIA: If subjects have known brain metastases (mets) that were treated previously with local therapies, surgery, and/or radiation, these lesions must be stable for at least 30 days prior to enrollment Brain tumors and/or brain metastases unless they are asymptomatic, stable on recent imaging (not dated more than 30 days from the inclusion date), and have not required active treatment in the last 6 months Patients with treated brain metastases will be re-screened (MRI brain or CT head with IV contrast); patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by MRI/CT for at least two weeks prior to the first dose of study drug), have no evidence of new or enlarging brain metastases and are off systemic steroids (=< 10 mg/day prednisone or equivalent) for at least one weeks prior to enrollment Patients with no history of CNS disease will not require a repeat MRI brain unless they have symptoms to suggest new brain metastases Participants with active brain metastases Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability. Note: Patients with previously treated brain metastases may participate, 2 weeks after gamma knife (or equivalent) or 4 weeks after whole brain radiotherapy (WBRT), provided they are stable (without evidence of progression by imaging and have not been using steroids for at least 7 days prior to study treatment Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms; participants with a history of treated central nervous system (CNS) metastases are eligible; treated brain metastases are defined as those having no evidence of progression for >= 1 month after treatment, and no ongoing requirement for corticosteroids, as ascertained by clinical examination and brain imaging (magnetic resonance imaging or computed tomography [CT] scan) completed during screening; any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 2 weeks prior to registration; treatment for brain metastases may include whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating physician; participants with CNS metastases treated by neurosurgical resection or brain biopsy performed within 2 months before day 1 will be excluded Patients must be free of active brain metastases by contrast-enhanced CT/magnetic resonance imaging (MRI) scans within 4 weeks prior to starting the study drugs; if known to have prior brain metastases, must not have evidence of active (enlarging and/or symptomatic lesions) brain disease on MRI evaluation within 2 weeks from stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT) treatment Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 2 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Has known active central nervous system (CNS) metastases and/or lymphomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 28 days prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include lymphomatous meningitis, which is excluded regardless of clinical stability Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for one month after treatment for the patient to be eligible; patients with surgically resected brain metastases are eligible Patients with known active central nervous system (CNS) metastases are ineligible; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. Patients with clinically symptomatic brain metastases or leptomeningeal disease; patients may be on a stable dose of corticosteroids to control brain metastases if they have been on a stable dose for two weeks prior to study treatment and are clinically asymptomatic Subjects with brain metastases must have completed treatment, either surgery or radiation, 4 weeks or longer prior to screening. A brain magnetic resonance imaging (MRI) demonstrating there is no current evidence of progressive brain metastases is required in subjects with previous brain metastasis. Patients with breast tissue expanders may have brain computerized tomography (CT) for assessment. Subjects with active brain metastases. Patients with known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they are asymptomatic or have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Has known or suspected active central nervous system (CNS) metastases and/or carcinomatous meningitis; patients with suspected central nervous system (CNS) disease should have lumbar puncture performed to exclude this possibility; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with controlled brain metastases are allowed on protocol if they had solitary brain metastases that was surgically resected or treated with radiosurgery or Gamma knife, without recurrence or edema for 1 month (4 weeks). Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to on-study date and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to leukapheresis; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with symptomatic uncontrolled brain metastases or spinal cord compressions. A scan to confirm the absence of brain metastases is not required. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 28 days prior to treatment. Untreated brain metastases, symptomatic brain metastases, brain metastases requiring steroids to manage symptoms, or treatment for brain metastases within 8 weeks prior to randomization; Patients with known brain metastases should be excluded from this clinical trial Has spinal cord compression or clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment (1 week for stereotactic radiotherapy). Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with active brain metastases should be excluded from this clinical trial. Has known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability. Patients with known brain metastases, as progressive neurologic dysfunction may develop that would confound the evaluation of neurologic and other adverse events Patients are excluded if they have active brain metastases or leptomeningeal metastases; subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for 4 weeks or more after treatment is complete and within 28 days prior to the first dose of nivolumab administration; there must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration Participants with brain or subdural metastases are not eligible unless the metastases are asymptomatic and do not require treatment or have been adequately treated by local therapy and have discontinued the use of corticosteroids for this indication for at least 28 days prior to study drug administration. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability Known clinically active brain metastases; prior evidence of brain metastasis successfully treated with surgery or radiation therapy will not be exclusion for participation as long as they are deemed under control at the time of study enrollment and there are no neurological signs of potential brain metastases Brain metastases or spinal cord compression are NOT permitted unless they have been treated with the patient's condition being stable clinically and radiologically for at least 28 calendar days and off steroids for at least 14 calendar days prior to the start of study treatment; patients with suspected or known brain metastases at screening should have a magnetic resonance imaging (MRI) (preferred) or CT brain/head, preferably with IV contrast, to assess baseline disease status Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging within four weeks prior to registration and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with history of brain metastases except those with meningeal carcinomatosis or leptomeningeal disease may be eligible for treatment a minimum of 1 week following completion of gamma knife or whole brain radiotherapy, or 4 weeks following surgical resection of brain metastasis provided post-treatment magnetic resonance (MR) scan reveals no evidence of active disease, and no ongoing need for systemic steroids Has known active central nervus system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to study treatment Known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging at least 4 weeks prior to first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to treatment Patient must be scheduled to undergo treatment with WBRT to manage the brain metastases Patient does not have any brain metastases in the genu Patients receiving prior stereotactic radiosurgery (SRS) for brain metastases are eligible Patients with brain metastases in the genu Patients with untreated symptomatic brain metastases; patients with treated brain metastases will be allowed if brain imaging obtained greater than 7 days from trial enrollment reveals stable disease; patients with small (< 3 mm) asymptomatic brain metastasis are allowed to enroll; patients on steroids doses higher than 10 mg of prednisone (or its equivalent) are excluded Patients who have a primary brain tumor (excluding meningiomas and other benign lesions), any brain metastases, leptomeningeal disease, seizure disorders not controlled with standard medical therapy, or history of stroke within the past year The total number of tumors requiring SRT must be =< 5\r\n* Note: Regardless of the number of brain metastases that will be treated with SRT, the brain metastases will be considered to be one tumor Patients with known brain metastases should be excluded from this clinical trial Patients with untreated brain metastases; treated brain metastases with radiation or surgery are allowed if: =< 3 cm in size AND =< 4 in number AND there is no evidence of progressive disease, on brain imaging >= 28 days after last day of central nervous system (CNS) treatment If history of brain metastases must be stable for at least 3 months after treatment – a brain computed tomography (CT) scan or MRI is only be required in subjects with known brain metastases at the time of enrollment or in subjects with clinical signs or symptoms suggestive of brain metastases Untreated brain metastases Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 28 days prior to registration and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to registration; this exception does not include known carcinomatous meningitis which is excluded regardless of clinical stability Presence or history of brain metastases Participants with known brain metastases should be excluded from this clinical trial Has known active central nervous system (CNS) lymphoma or lymphomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Patients with known brain metastases will be excluded from this clinical trial Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to enrollment in the study; patients with a history of brain metastases must have a head computed tomography (CT) or magnetic resonance imaging (MRI) scan with contrast to document stable disease for at least 24 weeks prior to enrollment in the study Brain metastases or spinal cord compression unless asymptomatic or treated and stable off steroids and anti-convulsants for at least 28 days prior to study treatment start. Patients with suspected brain metastases at screening should have a CT/MRI of the brain prior to study entry. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to study treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability; patients with prior CNS metastases treated w/ prior radiation therapy (RT) will also need all of the following: \r\n* 2 months off RT before starting study or 4 weeks following radiation therapy (XRT) if magnetic resonance imaging (MRI) is stable and the patient is off steroids\r\n* Baseline MRI with no edema and\r\n* Stable for at least 8 weeks Phase I Inclusion Criterion Only: Patients must have brain metastases, treated within 6 weeks of study entry with stereotactic radiosurgery (SRS) resection or whole brain radiation therapy (WBRT); a minimum interval of 3 weeks between completion of brain SRS and/or resection and 6 weeks for WBRT and the start of treatment in this trial will be observed to allow proper healing; the presence of concomitant extracranial metastatic disease is allowed for enrollment Phase II Inclusion Criterion Only: Patients must have 1-3 brain metastases, each < 3 cm by contrast MRI, treated within 6 weeks of study entry with SRS and/or resection; a minimum interval of 3 weeks between completion of brain SRS and/or resection and the start of treatment in this trial will be observed to allow proper healing; patients with 4 or 5 brain metastases will be evaluated case by case and may be eligible pending on the total field radiated; the presence of concomitant extracranial metastatic disease is allowed for enrollment Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible; patients with surgically resected brain metastases are eligible Patients with clinically active brain metastases. However, patients with previously currently stable brain metastases on medication (i.e., steroids and/or anti-seizure medications) may be enrolled after consultation with the Medical Monitor. Subjects with a history of known central nervous system (CNS) metastases must have documentation of stable or improved brain imaging for at least 2 weeks after completion of definitive treatment; definitive treatment may include surgical resection, whole brain irradiation, and/or stereotactic radiation therapy Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 2 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Previous radiation to the brain, including WBRT or brain radiosurgery Patients with previously untreated brain metastases should be excluded; patients with treated and stable (> 4 weeks) brain metastases may be eligible for enrollment Untreated brain metastases, if not planned to be treated in this course of radiation therapy Symptomatic brain metastases requiring immediate local interventions such as craniotomy or stereotactic radiosurgery (SRS) Untreated brain metastases Known or suspected brain metastases or spinal cord compression, unless the condition has been asymptomatic, has been treated with surgery and/or radiation, and has been stable without requiring corticosteroids nor anticonvulsant medications for at least 4 weeks prior to the first dose of study medication. Patients with history of brain metastases should undergo brain imaging within 4 weeks of therapy initiation and at each restaging All subjects with brain metastases, except those meeting the following criteria:\r\n* Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment\r\n* No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable)\r\n* Subjects must be either off steroids or on a stable or decreasing dose of =< 10 mg daily prednisone (or equivalent) Has known active central nervous system (CNS) metastases and/or lymphomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include lymphomatous meningitis which is excluded regardless of clinical stability Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; active CNS metastases will be defined as brain lesions that 1) require intervention with surgery, stereotactic radiosurgery (SRS), or whole brain radiotherapy (WBRT) or 2) require anti-epileptic therapy, systemic steroid treatment, or intrathecal therapy; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks after completion of focal therapy brain metastases and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Participants with symptomatic brain metastases will be excluded from this clinical trial; subjects with asymptomatic, stable brain metastases and subjects who, if they have been previously treated for these conditions that are asymptomatic in the absence of corticosteroid therapy are allowed to enroll; brain metastasis must be stable with verification by imaging (brain magnetic resonance imaging [MRI] completed at screening demonstrating no current evidence of progressive brain metastases); if asymptomatic brain metastasis are first identified on the required pre-study scans, another set of scans must be completed to confirm that they are stable Participants with known brain metastases should be excluded from this clinical trial Documented brain metastases that are untreated, symptomatic, or require therapy to control symptoms; participants with previously diagnosed brain metastases are eligible if they have completed treatment at least one month prior to trial registration, are neurologically stable, and have recovered from effects of radiotherapy or surgery\r\n* Any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 2 weeks before the first study drug\r\n* Treatment for brain metastases may have included whole brain radiotherapy, radiosurgery, or a combination as was deemed appropriate by the treating physician\r\n* Patients who meet the above criteria and are clinically stable on anticonvulsant medication are eligible only if their anti-convulsant does not alter hepatic cytochrome P450 activity in a way that might interfere with metabolism of abemaciclib Brain metastases or a history of brain metastases Patients with known brain metastases with progressive neurologic dysfunction, requirement of steroids and lack of improvement on head imaging obtained prior to consent to this clinical trial should be excluded; patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging using the identical imaging modality for each assessment, either magnetic resonance imaging [MRI] or computed tomography [CT] scan, for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; patients with carcinomatosis meningitis should also be excluded Patients are excluded if they have active brain metastases or leptomeningeal metastases; subjects with brain metastases are eligible if metastases have been treated and there is no imaging evidence of progression for 28 days after treatment is complete and within 28 days prior to the first dose of nivolumab administration Patients with active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 4 weeks prior to trial treatment Known central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable without evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; the use of topical steroids is permitted Subjects with radiographically stable treated brain metastases are eligible but must not have been on steroid therapy for at least 4 weeks Known untreated or symptomatic brain metastases Brain metastases unless previously treated and well controlled for at least 3 months Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids Patients with known brain metastases will be excluded from this clinical trial Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events Uncontrolled brain metastases; patients treated with radiation >= 4 weeks prior with follow up imaging showing control are eligible Patients with symptomatic brain metastases are excluded; patients with asymptomatic and treated central nervous system (CNS) metastases may participate in this trial; the patient must have completed any prior treatment for CNS metastases > 28 days prior to study entry including radiotherapy or surgery; steroids for the treatment of brain metastasis are not permitted, and patients must be stable off steroid treatment for 4 weeks prior to enrollment Previously treated (surgery and/or radiation therapy) or untreated brain metastases are eligible, provided that patients are asymptomatic and not requiring escalating doses of corticosteroids Presence of symptomatic brain metastases or brain metastases requiring escalating doses of corticosteroids to control neurological symptoms Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with known symptomatic brain metastases requiring systemic corticosteroids; patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable; mild neurological deficit is allowed, if it does not interfere with the ability to judge the safety on the trial Treated stable brain metastases are allowed, as long as patient does not require steroids or anti-seizure medications AND asymptomatic and off systemic corticosteroids and/or enzyme-inducing anti-epileptic medications for brain metastases for >14 days prior to registration. Patients with known extrathoracic metastases, including brain metastases, or known malignant pleural or pericardial effusion Patients with treated, stable, and asymptomatic brain metastases are eligible Untreated, progressing, or symptomatic brain metastases Symptomatic brain metastases or leptomeningeal (LM) disease requiring corticosteroids for symptom management; asymptomatic brain metastases or LM will be allowed on study Metastases to brain per prior clinical evaluation; Active central nervous system (CNS) metastases\r\n* NOTE: Subjects who are symptomatic or have not undergone prior brain imaging must undergo a head computed tomography (CT) scan or brain magnetic resonance imaging (MRI) within 28 days prior to registration to exclude brain metastases\r\n* NOTE: A subject with prior brain metastasis may be considered if they have completed their treatment for brain metastasis at least 4 weeks prior to study registration, have been off of corticosteroids for >= 2 weeks, are asymptomatic, and there is no evidence of progression on brain imaging (CT or MRI) Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis\r\n* Note: Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Participants with history of brain metastases who have not shown clinical and radiographic stable disease for at least 28 days after definitive therapy. Patients with symptomatic brain metastases will be excluded from trial secondary to poor prognosis; however, patients who have had treatment for their brain metastasis and whose brain disease has remained stable for 3 months without steroid therapy may be enrolled All subjects with brain metastases, except those meeting the following criteria:\r\n* Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment \r\n* No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable)\r\n* Subjects must be either off steroids or on a stable or decreasing dose of =< 10 mg daily prednisone (or equivalent) Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable for 6 months (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Subjects with brain metastases Patients with clinically symptomatic brain metastases or who required treatment for brain metastases within 4 weeks of registration (stable sequelae acceptable if treatment has been completed; these lesions cannot be used as target lesions) Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Brain metastases are allowed, as long as they are stable and do not require treatment with anticonvulsants or escalating doses of steroids Has known primary brain tumor, active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless or clinical stability. Subjects with previously treated brain or central nervous system (CNS) metastases are eligible provided that the subject has recovered from any acute effects of radiotherapy and is not requiring steroids, and any whole brain radiation therapy was completed at least 4 weeks prior to study drug administration, or any stereotactic radiosurgery was completed at least 2 weeks prior to study drug administration; liver metastases will not be included as part of the radiated lesions to be treated Patient with a known history or evidence of brain metastases All subjects with brain metastases, except those meeting the following criteria:\r\n* Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment \r\n* No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable)\r\n* Subjects must be either off steroids or on a stable or decreasing dose of < 10 mg daily prednisone (or equivalent) Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability; known brain metastases are considered active, if any of the following criteria is applicable:\r\n* Brain imaging during screening demonstrates progression of existing metastases and/or appearance of new lesions compared to brain imaging performed at least 4 weeks earlier\r\n* Neurological symptoms attributed to brain metastases have not returned to baseline\r\n* Steroids were used for brain metastases within 28 days of randomization Known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to the first dose of study drug; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Unresectable metastases Patients with uncontrolled brain metastases; patients with brain metastases must be asymptomatic and off corticosteroids for at least one week Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with known brain metastases should be excluded from this clinical trial No known or suspected brain metastases (NOTE: patients with treated epidural disease are allowed) Active central nervous system metastases and/or carcinomatous meningitis\r\n* Note: Patients with untreated brain metastasis will be excluded; patients with previously treated brain metastases may participate provided they meet the following criteria:\r\n** Inactive (without evidence of progression which is documented by CT or MRI within 90 days prior to registration), AND\r\n** On =< 10 mg/day prednisone or equivalent for at least 28 days prior pre-registration Subjects with detectable cerebrospinal fluid malignant cells or known brain metastases, or with a history of cerebrospinal fluid malignant cells or brain metastases. Participants with known brain metastases from solid tumors should be excluded from this clinical trial Symptomatic or unstable brain metastases. Patients with known brain metastases should be excluded from this clinical trial Patients with active brain metastases; a scan to confirm the absence of brain metastases is not required for asymptomatic patients Has untreated brain metastasis. In the case of a solitary brain metastasis which has been resected, there must be evidence of a disease-free interval of at least 3 months post-surgery. For brain metastases treated with whole brain or stereotactic radiation therapy, brain imaging must be stable > 3 months. All subjects previously treated for brain metastases must be stable off corticosteroid therapy for at least 28 days prior to C1D1. Patients with active brain metastases or carcinomatous meningitis are excluded from this clinical trial; patients with treated brain metastases, whose brain metastatic disease has remained stable for greater than or equal to 4 weeks without requiring steroid and anti-seizure medications are eligible to participate Patients with untreated brain metastases, spinal cord compression, or evidence of symptomatic brain metastases or leptomeningeal disease as noted on computed tomography (CT) or magnetic resonance imaging (MRI) scans should be excluded from this clinical trial; screening brain MRI (or CT if MRI contraindicated) will be required for patients with recurrent NSCLC, TNBC, or SCLC; brain MRI (or CT if MRI contraindicated) is required for PDAC if clinically suspected by patient’s symptoms or neurological exam; should patient found to have brain metastasis, treatment of brain metastasis must precede the participation in this study; for patients with known and treated brain metastases is allowed in this study if they fulfill the following criteria:\r\n* The lesions have improved or remained stable radiographically and clinically for at least 6 weeks after completion of brain irradiation or stereotactic brain radiosurgery and off steroids for at least 6 weeks Prior whole brain irradiation Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids Patients with active brain metastases should be excluded from this clinical trial; patients with prior history of brain metastasis who have undergone local therapy (i.e., metastasectomy and/or radiation) and show no evidence of local recurrence or progression over the past 6 months are eligible Patients with controlled brain metastases are allowed on protocol if they had solitary brain metastases that was surgically resected or treated with radiosurgery or gamma knife, without recurrence or edema for 1 month (4 weeks) Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases Patients with known brain metastases are excluded from this clinical trial; patients with primary brain tumors amenable to surgery are allowed on this protocol Patients with known brain metastases Known active and/or untreated brain metastases Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 14 days prior to trial treatment; this exception does not include carcinomatous meningitis, which is\r\nexcluded regardless of clinical stability Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids Clinical stability of brain metastases for at least 4 weeks prior to first day of study therapy. All subjects with brain metastases, except those meeting the following criteria: \r\n* Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment\r\n* No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable)\r\n* Subjects must be either off steroids or on a stable or decreasing dose of =< 10 mg daily prednisone (or equivalent) Symptomatic brain metastases Patients may have metastases, with newly identified peripheral metastases Patients who have a history of brain metastasis are eligible for the study provided that all the following criteria are met:\r\n* Brain metastases which have been treated\r\n* No evidence of disease progression for >= 3 months or hemorrhage after treatment\r\n* Off-treatment with dexamethasone for 4 weeks before administration of the first dose of TAK-228\r\n* No ongoing requirement for dexamethasone or anti-epileptic drugs Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with untreated brain metastases and patients who have had brain metastases re-treated with radiation will be excluded; patients whom have either midline shift, or any signs of herniation (even if disease has been treated with GK) will be excluded; subjects with previously treated brain metastases may participate provided they are 1) stable (without clinical evidence of progression) 2) are out at least 10 days from CNS radiation and 3) and are not using steroids as part of treatment for their brain lesions for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Subjects with no brain metastases or a history of previously treated brain metastases who have been treated by surgery or stereotactic radiosurgery (SRS) at least 4 weeks prior to enrollment and have a baseline MRI that shows no evidence of active intracranial disease Patients with clinically active brain metastases (known or suspected) are excluded unless the brain metastases have been previously treated and are considered stable. Stable brain metastases are defined as no change on CT scan or magnetic resonance imaging (MRI) scan for a minimum of 2 months AND no change in steroid dose for a minimum of 4 weeks, unless change due to intercurrent infection or other acute event Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability Patients with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids, anti-convulsants or have been on stable dose of corticosteroids for at least 4 weeks before starting study treatment; any symptoms attributed to brain metastases must be stable for at least 4 weeks before starting study treatment Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Subjects with suspected or known brain metastases should be excluded from this clinical study because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Known brain metastases Patients with previously treated (with radiation or surgery) brain metastases that are stable are allowed; patients with stable or progressing metastases must have metastases =< 1.5 cm, be asymptomatic, and either not be on steroids or be on 10 mg prednisone equivalent or less Current or previously treated brain or leptomeningeal metastases Current or previously treated brain or leptomeningeal metastases Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids Untreated brain metastasis(es) that may be considered active. Patients with previously treated brain metastases may participate provided they are stable (i.e., without evidence of Progression of Disease by imaging for at least 4 weeks prior to the first dose of trial treatment, and any neurologic symptoms have returned to baseline), and there is no evidence of new or enlarging brain metastases Patients with known brain metastases should be excluded from this clinical trial Patients with a history of seizure disorder, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation Participants with treated brain metastases are allowed; radiation must be completed at least 2 weeks prior to pembrolizumab dosing and participants must not require ongoing steroids; participants with untreated brain metastases that are all < 5 mm with no clinical symptoms or vasogenic edema may be allowed on study on a case-by-case basis on discussion with sponsor; these participants will require MRI monitoring every 6 weeks to ensure stability Symptomatic or unstable brain metastases; (Note: asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroid for treatment of brain metastases for at least 14 days [or decreasing dose of corticosteroid] are eligible to participate in the study); patients with primary central nervous system tumors are eligible Have no known metastases Brain metastases unless asymptomatic, stable and not requiring steroids for at least 2 weeks Previously treated brain metastases (surgery and/or radiation therapy) are eligible, provided that patients are asymptomatic and not requiring corticosteroids Patients with melanoma brain metastases are allowed; subjects with brain metastases are eligible if (a) metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for 4 weeks after treatment is complete and within 28 days of the first dose of nivolumab administration; or (b) if they are untreated but asymptomatic or c) if they are untreated and symptomatic but symptoms are controlled on stable or decreasing doses of steroids for 14 days prior to drug administration; patients are excluded if they require high doses of systemic corticosteroids (> 8 mg equivalent of dexamethasone) to control central nervous system (CNS) symptoms Active leptomeningeal metastases Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids Patients with symptomatic uncontrolled brain metastases are excluded; (patients with stable treated or asymptomatic untreated brain metastasis not requiring glucocorticoids are allowed) Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Postoperative patients with resected brain metastases are eligible Greater than 10 brain metastases; excluding previously treated and stable brain metastases Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by magnetic resonance imaging [MRI] for at least two weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are using no steroids for at least three days prior to study medication Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids Patients with brain metastases. Patients with uncontrolled brain metastases; patients with brain metastases must have stable neurologic status following local therapy (surgery or radiation) for at least 2 weeks without the use of steroids or on stable or decreasing dose of < 10mg daily prednisone (or equivalent), and must be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; patients with a history of carcinomatous meningitis are not eligible History or evidence of brain metastases Patients with three or fewer brain metastases that have been treated with surgery or stereotactic radiosurgery are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for one month before protocol treatment; patients with surgically resected brain metastases are eligible Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible; lesions > 1 cm that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible; patients with surgically resected brain metastases are eligible Known active central nervous system (CNS) metastases and/or carcinomatous meningitis\r\n* Subjects with previously treated brain metastases may participate provided they are stable, have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with known brain metastases Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability Prior treated brain metastases are allowed; however, prior treated brain metastases must be without magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks and off systemic steroids for at least 2 weeks before study drug administration Symptomatic or untreated brain metastases Participants with known brain metastases should be excluded from this clinical trial Patients with known brain metastases should be excluded Patients with known brain metastases should be excluded from this clinical trial; patients with brain metastases that are stable after >= 1 year after primary surgery or radiation will not be excluded Documented evidence of distant metastases Known clinically active brain metastases; prior evidence of brain metastasis successfully treated with surgery or radiation therapy will not be exclusion for participation as long as they are deemed under control at the time of study enrollment and there are no neurological signs of potential brain metastases 3 or fewer brain metastases; Note: if lesions are symptomatic or greater than or equal to 1 cm each, these lesions must have been treated and stable for 3 months for the patient to be eligible PHASE I: Patients with treated brain metastases (surgery, whole or stereotactic brain radiation) are allowed provided the lesions have been stable for at least 2 weeks and the patient is off steroids or is on a stable dose of steroids; patients with brain metastases should not require use of enzyme-inducing antiepileptic drugs (e.g., carbamazepine, phenytoin, or phenobarbital) within 14 days before first dose and during study; use of newer antiepileptics that do not produce enzyme induction drug-drug interactions (DDIs) is allowed PHASE II SCLC: Patients with treated brain metastases (surgery, whole or stereotactic brain radiation) are allowed provided the lesions have been stable for at least 2 weeks and the patient is off steroids or is on a stable dose of steroids; patients with brain metastases should not require use of enzyme-inducing antiepileptic drugs (e.g., carbamazepine, phenytoin, or phenobarbital) within 14 days before first dose and during study; use of newer antiepileptics that do not produce enzyme induction drug-drug interactions (DDIs) is allowed Evidence of distant metastases Patients who have undergone a resection for brain metastases will be eligible for participation if they have any residual metastases present on post operative magnetic resonance imaging (MRI) of the brain Patients with leptomeningeal metastases Patients with brain metastases involving the brainstem or chiasm Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with treated and clinically stable brain metastases are allowed Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to study drug administration and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to study drug administration; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids For subjects in cohort 2 (small cell malignancies of non-pulmonary origin), confirmation of no brain metastases via imaging Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Subjects with untreated or uncontrolled brain metastases or evidence of leptomeningeal disease; patients with asymptomatic brain metastases or previously treated brain metastases that are stable (i.e. not requiring corticosteroids) at the time of study start will be eligible Patients who have a history of brain metastasis are eligible for the study provided that all the following criteria are met:\r\n* Brain metastases which have been treated\r\n* No evidence of disease progression for >= 4 weeks or hemorrhage after treatment\r\n* Off-treatment with dexamethasone for 2 weeks before administration of the first dose of MLN0128\r\n* No ongoing requirement for dexamethasone or anti-epileptic drugs Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with both brain and spine metastases will be excluded from the trial Active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to enrollment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to enrollment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases EXCLUSION CRITERIA FOR TNBC: Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to enrollment and any neurologic symptoms have returned to baseline) and have no evidence of new or enlarging brain metastases Subject has known brain metastases; presence of brain metastases should be excluded from this clinical trial Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids Primary central nervous system (CNS) malignancies or CNS metastases, including leptomeningeal metastases, are not allowed; subjects with previously treated brain metastases will be allowed if the brain metastases have been stable for at least 3 months following prior treatment (radiotherapy or surgery) Active uncontrolled or symptomatic brain metastases; previously treated and clinically stable, as per investigator’s judgment, brain metastases are permitted Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Known active brain or leptomeningeal metastases (defined as symptomatic metastases) or continued requirement for glucocorticoids for brain or leptomeningeal metastases; treated, asymptomatic metastases are permitted provided the patient has been off steroids for at least 4 weeks prior to day 1 of study drug Known brain metastases; patients with known brain metastases must be excluded from this clinical trial Metastatic melanoma or non-squamous NSCLC with untreated brain metastases A history of previously treated brain metastases is allowed, provided that at least 7 days have lapsed between radiation and initiation of pembrolizumab; any brain metastasis >= 20 mm or causing symptoms must be treated with local therapy (i.e. radiation or surgical resection, as clinically appropriate) prior to study enrollment; any lesion present at the time of whole brain radiotherapy (WBRT) or included in the stereotactic radiotherapy field (or within 2 mm of the treated lesion) will NOT be considered evaluable unless it is new or documented to have progressed since treatment Symptomatic brain metastases; any neurologic symptoms present must have resolved with local therapy by the time of administration of study drug Patients with brain metastases for whom complete surgical resection is clinically appropriate Has known active central nervous system metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for brain metastases for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Brain metastases unless previously treated and well controlled for at least 3 months Known active central nervous system (CNS) disease - If patient has history of brain metastases, the brain lesions must have been treated with radiation and/or surgery- patients should be neurologically stable and on a stable or tapering dose of corticosteroids Subjects with brain metastases are eligible if treated (whole brain radiotherapy, stereotaxic radiotherapy, surgery) and have no symptoms (except for signs and symptoms related to central nervous system therapy) for at least 2 weeks before initiation of allocated treatment and are not taking any forbidden medications. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Clinically active brain metastases; radiological documentation of absence of active brain metastases at screening is required for all patients; prior evidence of brain metastasis successfully treated with surgery or radiation therapy will not be exclusion for participation as long as they are deemed under control at the time of study enrollment The subject has active brain metastases or epidural disease All brain metastases must be outside the brain stem (midbrain, pons and medulla) Patient must have 10 or less brain metastases Known active central nervous system metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of MK-3475 [pembrolizumab] and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids in doses greater than 10 mg of prednisone daily (or equivalent) for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Symptomatic or unstable brain metastases; (Note: asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days prior to registration are eligible to participate in the study) Known active central nervous system metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of MK-3475 and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Brain metastases meeting either of the following exclusion criteria:\r\n* Untreated brain metastases\r\n* After completion of brain-directed therapy, the patient has not been able to tolerate discontinuation of steroids or a decrease in steroid dose Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible; patients with surgically resected brain metastases are eligible Patients with untreated brain metastases are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events Patients with known brain metastases or leptomeningeal metastases should be excluded from this clinical trial; patients with other extrapleural metastases are included in this study Patients with symptomatic brain metastases are excluded; patients with asymptomatic and treated central nervous system (CNS) metastases may participate in this trial; the patient must have completed any prior treatment for CNS metastases > 28 days prior to study entry, including radiotherapy or surgery; steroids for the treatment of brain metastasis are not permitted Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Prior treated brain or meningeal metastases must be without MRI evidence of progression for at least 8 weeks and off systemic steroids for at least 2 weeks prior to screening/baseline. Patients are excluded if they have active brain metastases or leptomeningeal metastases; subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks after treatment is complete and within 28 days prior to the first dose of nivolumab administration; there must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration Patients with known brain metastases should be excluded from this clinical trial Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids The patient has symptomatic brain metastases; asymptomatic brain metastases are permitted provided that there is no steroid requirement, no more than 4 metastases detected on standard MRI imaging, no metastatic brain lesion that is > 3 cm in size, and no lepto-meningeal disease Prior whole brain irradiation REGORAFENIB EXCLUSION CRITERIA: Known symptomatic brain metastases leptomeningeal involvement on unstable/increasing doses of steroid\r\n* Patients with asymptomatic brain metastases or leptomeningeal carcinomatosis may be enrolled at the discretion of the Sponsor as long as the patient is in clinically stable condition and, if requiring steroid, must be on a stable or decreasing dose for at least 5 days prior to regorafenib administration Known brain metastases Known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Subjects with known active brain metastases will be excluded from this clinical trial. Patients with brain metastases that have been treated and stable for >= 30 days following treatment will be eligible. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Patients may have parenchymal brain metastases if stable (no evidence of progression) for at least 1 month after local therapy (radiation or surgery); leptomeningeal disease is excluded; must have completed any prescribed steroid taper prior to registration No evidence of distant metastases More than four additional diagnosed brain metastases Have a history of or current evidence of intracranial disease; patients with brain metastases must be excluded from this clinical trial Progressive, symptomatic untreated brain metastases Prior whole brain irradiation Has known active CNS or any leptomeningeal metastasis of primary extra-cranial tumor - NOTE: Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging 4 weeks prior to the first dose of study drug and any neurologic symptoms have stabilized), have no evidence of new or enlarging brain metastases, and are on stable or tapering doses of steroids for at least 7 days prior to first dose of study drug. Patients with known brain metastases should be excluded from this clinical trial Patients are excluded if they have active brain metastases or leptomeningeal metastases; subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for 2 weeks of more after treatment is complete and within 28 days prior to the first dose of nivolumab administration; there must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration Patients with controlled brain metastases are allowed on protocol if they had solitary brain metastases that was surgically resected without recurrence or treated with stereotactic radiosurgery (SRS) without progression x 4 weeks Must not have untreated brain metastases Prior whole brain irradiation Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to initiation of lymphodepletion Patients with known brain metastases Known or suspected leptomeningeal disease; patients with metastases to the brain stem, midbrain, pons or medulla Known or suspected untreated brain metastases; patients with radiographically stable, asymptomatic previously irradiated lesions are eligible provided patient is >= 4weeks beyond completion of cranial irradiation and >= 3 weeks off of corticosteroid therapy at the time of study intervention Subjects with symptomatic brain metastases will be excluded from trial secondary to poor prognosis; however, subjects who have had treatment for their brain metastasis and whose brain disease is stable without steroid therapy for 1 week or on physiologic doses of steroids may be enrolled Untreated brain metastases, treated brain metastases that are not stable, leptomeningeal disease, or seizures uncontrolled with standard medical therapy PHASE II STUDY NON-SMALL CELL LUNG CANCER (COHORT 2; MEDI+O AND MEDI+C) AND SMALL CELL LUNG CANCER (COHORT 3; MEDI+O ONLY) ELIGIBILITY CRITERIA:\r\nPatients with symptomatic brain metastases will be excluded from trial secondary to poor prognosis; however, patients who have had treatment for their brain metastasis and whose brain disease is stable without steroid therapy for 2 weeks may be enrolled; baseline imaging to rule out brain metastases is not required for screening, but should be performed prior to study enrollment if clinically indicated PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nCNS disease: subjects with symptomatic brain metastases will be excluded from trial secondary to poor prognosis; however, subjects who have had treatment for their brain metastasis and whose brain disease is stable without steroid therapy for 4 weeks may be enrolled; baseline imaging to rule out brain metastases is not required for screening, but should be performed prior to study enrollment if clinically indicated Patients may have treated and stable brain metastases; they must be off steroids and must have had stable brain metastases for at least 6 months Subject has known active central nervous system (CNS) involvement; the subject has untreated brain or meningeal metastases; computed tomography (CT) scans are not required to rule out brain or meningeal metastases unless there is a clinical suspicion of central nervous system disease; subjects with treated brain metastases that are radiographically or clinically stable for at least 4 weeks after therapy and have no evidence of cavitation or hemorrhage in the brain lesion(s) are eligible, providing that they are asymptomatic, and do not require corticosteroids (must have discontinued steroids at least 1 week prior to study drug administration) Subjects with brain metastases should be excluded from this clinical trial unless all the metastasis are treated surgically or radio-surgically Meningeal metastases or brain metastases that are symptomatic or untreated\r\n* Note: patients who are asymptomatic and have had post-treatment imaging that indicates stable brain disease are eligible; (patients with meningeal metastasis are not eligible even if stable following treatment); also, note that brain imaging is required within 8 weeks prior to initiation of study therapy Patients with 1?10 newly diagnosed brain metastases deemed to be eligible for radiosurgery\r\n* Prior whole brain radiotherapy (RT) and radiosurgery (to areas outside of the newly diagnosed brain metastases requiring radiosurgery) is allowed Leptomeningeal metastases Have had known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for CNS involvement for at least one week prior to trial treatment; patients with primary brain tumors are not eligible; however, as patients are completing abiraterone therapy, they will be allowed to continue up to 10 mg/day of prednisone Patients with untreated brain metastases, spinal cord compression, or evidence of symptomatic brain metastases or leptomeningeal disease as noted on computed tomography (CT) or magnetic resonance imaging (MRI) scans should not be included on this study; screening imaging to rule out brain metastases is not required for screening, but should be performed prior to study enrollment if clinically indicated; patients with treated brain metastases and resolution of any associated symptoms must demonstrate stable post-therapeutic imaging for at least 6 months following therapy prior to starting study drug Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Subject has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; note: subjects with previously treated brain metastases will be eligible to participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Subjects with known metastases Patients with symptomatic or recurrent brain metastases should be excluded from this clinical trial Patients with known active brain metastases; (subjects with previously treated brain metastases are eligible provided they are stable [defined as without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment] and neurologic symptoms have returned to baseline) Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate if they are stable, and have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Patients with known, untreated or progressive brain metastases will be excluded from this clinical trial Symptomatic and/or untreated Brain Metastases Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Brain or central nervous system (CNS) metastases \r\n* Exception: Adequately treated brain metastases documented by baseline computed tomography (CT) or magnetic resonance imaging (MRI) scan that have not progressed since previous scans and do not require corticosteroids (except prednisone =< 5 mg/day or equivalent) for management of CNS symptoms; a repeated CT or MRI following the identification of CNS metastases (obtained at least 2 weeks after definitive therapy) must document adequately treated brain metastases\r\n* Subjects with leptomeningeal carcinomatosis are not permitted Patients must have 1-5 brain metastases total Untreated or brain metastasis causing any symptoms, such as neurologic deficits or headache; individuals with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of study drug and any neurologic symptoms have returned to baseline and whole brain radiation or stereotactic radiosurgery completed over 4 weeks prior to registration), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to study treatment Patients with known brain metastases should be excluded from this clinical trial Known active central nervous system (CNS) metastases; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 28 days prior to treatment Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Current symptomatic brain metastases; if previously present, the metastases must have been treated at least two months before participation in this study; CT or MRI scan of the brain is mandatory to assess the presence or not of brain metastases Gliomas are excluded, as well as any history of brain metastases, seizures or underlying brain injury Known untreated brain or leptomeningeal metastasis\r\n* Patients with brain metastases are eligible if metastases have been adequately treated and neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least two weeks prior to C1D1 Presence of brain metastases Patients with known brain metastases should be excluded from this clinical trial Patients with known brain metastases should be excluded from this clinical trial Patients with uncontrolled brain metastases; patients with brain metastases must be asymptomatic and off corticosteroids for at least one week Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Symptomatic brain metastases; patients with known brain metastases are eligible if the metastases are asymptomatic and previously treated Patients with any evidence of distant metastases Must not have known brain metastases Patients with symptomatic or progressive brain metastases are ineligible; subjects with treated brain metastases are eligible if they have no radiographic or other signs of progression in the brain for >= 4 weeks after completion of local therapy Symptomatic brain metastases or brain metastases requiring chronic steroids to control symptoms. Brain metastases or bone metastases; patients with brain metastases must have received treatment for them (resection or stereotactic radiosurgery [SRS]) and these metastatic foci must be stable for 8 weeks prior to starting study drug Patients with untreated brain metastases or who have signs/symptoms attributable to brain metastases and have not been assessed with radiologic imaging to rule out the presence of brain metastases; patients with brain metastases that have been definitively treated and on stable or decreasing dose of steroid within 4 weeks of starting study treatment will be eligible Patients who have a primary brain tumor (excluding meningiomas and other benign lesions), any brain metastases, leptomeningeal disease, seizure disorders not controlled with standard medical therapy, history of stroke within the past year Distant metastases Symptomatic brain metastases; patients with known brain metastases are allowed if they are asymptomatic Evidence of distant metastases Patients with known brain metastases should be excluded from this clinical trial Evidence of distant metastases Patients with known brain metastases should be excluded from this clinical trial Subjects with known brain metastases should be excluded from this clinical trial No evidence of distant metastases Previously treated patients with non-squamous NSCLC who have had brain metastases at any point in their treatment history are eligible for enrollment on this clinical trial; (patients must have received at least one regimen for systemic disease which may be cytotoxic or oral tyrosine kinase inhibitor therapy)\r\n* Patients with clinically asymptomatic (no requirement for systemic corticosteroids) untreated brain metastases will be allowed on trial at the discretion of the treating physician\r\n* Patients who have undergone treatment for their brain metastases with whole brain radiotherapy, stereotactic radiosurgery, or surgical resection must be clinically stable and recovered from all procedures at the time of study enrollment Patients with untreated brain metastases should be excluded from this clinical trial Patients with locally treated, stable, and/or asymptomatic brain metastases are eligible Patients may be enrolled with a history of treated brain metastases that are clinically stable for >= 4 weeks prior to start of study treatment Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by magnetic resonance imaging [MRI] for at least four weeks prior to the first dose of study drug), have no evidence of new or enlarging brain metastases and are off systemic steroids (=< 10 mg/day prednisone or equivalent) for at least two weeks prior to enrollment Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible; patients with surgically resected brain metastases are eligible A history of previously treated brain metastases is allowed, provided that at least 14 days have lapsed between radiation and initiation of MK-3475; any lesion present at the time of whole-brain radiotherapy (WBRT) or included in the stereotactic radiotherapy field (or within 2mm of the treated lesion) will NOT be considered evaluable unless it is new or documented to have progressed since treatment Patients with brain metastases for whom complete surgical resection is clinically appropriate Patients with known brain metastases should be excluded from this clinical trial; exception: patients with brain metastases will be allowed on study if they have clinically controlled neurologic symptoms, defined as surgical excision and/or radiation therapy followed by 21 days of stable neurologic function and no evidence of central nervous system (CNS) disease progression as determined by computed tomography (CT) or magnetic resonance imaging (MRI) within 21 days prior to the first dose of study drug No prior radiotherapy to the brain The subject has active brain metastases or epidural disease who have not been treated with radiation therapy (Note: subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 2 months before starting study treatment; (baseline brain imaging with contrast-enhanced CT or MRI scans for subjects with known brain metastases is required to confirm eligibility) Patients with brain metastases may participate in this clinical study provided that symptoms have been controlled with standard therapies and/or appropriate medications; the principal investigator (P.I.) will carefully evaluate the suitability of patient participation when brain metastases are present Patients with known brain metastases (treated or not) will be excluded Presence of brain metastases Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible; patients with surgically resected brain metastases are eligible Patient with a known history or evidence of brain metastases Patients with symptomatic brain involvement Symptomatic brain metastases (baseline CT scan is not required in asymptomatic patients) Evidence of distant metastases Must not have leptomeningeal metastases. Patients with known brain metastases should be excluded from this clinical trial Subjects with brain metastases are excluded from this clinical trial unless all the metastases are adequately treated with surgery or radiation\r\n* Follow-up imaging showing treatment adequacy is not required Magnetic resonance imaging (MRI) evidence of 1-4 brain metastases, with at least one lesion > 20 mm and =< 50 mm in maximal diameter and determined to be appropriate for SRS and gross total resection; all other brain metastases are appropriate for SRS Prior whole brain radiotherapy Patients with known brain metastases should be excluded from this clinical trial Untreated, symptomatic, or progressive brain metastases; participants must have no radiographic or other signs of progression in the brain for >= 1 month after completion of local therapy; any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 4 weeks prior to first study treatment Patients with known brain metastases should be excluded from this clinical trial Patients with known MIBG-avid parenchymal brain metastases are excluded Any patient undergoing SRS for brain metastases Patients may have had prior therapy including:\r\n* Whole brain radiation therapy (WBRT) > 3 months ago\r\n* SRS to other brain metastases Leptomeningeal metastases Subjects with known brain metastases should be excluded from this clinical trial Prior whole brain irradiation Clinically active brain metastases; radiological documentation of absence of active brain metastases at screening is required for all patients; prior evidence of brain metastasis successfully treated with surgery or radiation therapy will not be exclusion for participation as long as they are deemed under control at the time of study enrollment Known brain metastases, unless previously treated and asymptomatic for 3 months and not progressive in size or number for 3 months History of brain metastases within the last four years Documented evidence of distant metastases Symptomatic brain metastases Patients with history or evidence upon physical examination of central nervous system (CNS) disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases Evidence of distant metastases or distant leptomeningeal metastases at the time of diagnosis Evidence of distant metastases Subjects with no brain metastases or a history of previously treated brain metastases who:\r\n* Have been treated by surgery or stereotactic radiosurgery (SRS) at least 4 weeks prior to enrollment\r\n* AND have a baseline magnetic resonance imaging (MRI) that shows no evidence of active intercranial disease\r\n* AND have not had treatment with steroids for brain metastases within 1 week of study enrollment No more than 1 Brain Met can be treated under this protocol Patients may not have previously been treated with > 1 course of radiotherapy to the brain Patients may not have previously been treated with radiosurgery to the brain Patients must have histologically confirmed malignancy with brain metastases and are being recommended palliative WBRT Subjects with known brain metastases. Symptomatic brain metastases Patients with brain metastases for whom complete surgical resection is clinically appropriate Documented and/or symptomatic or known brain or leptomeningeal metastases Known uncontrolled brain, leptomeningeal or epidural metastases (unless treated and well controlled for at least 4 weeks prior to Cycle 1 Day 1). Controlled brain metastases that require continuous high dose corticosteroid use within 4 weeks of Day For Parts A, B, C, D, E: Have evidence of leptomeningeal metastases. Note: discrete dural metastases are permitted. Patients with prior history of treated brain metastases who are off steroids and have stable metastatic brain disease for at least 3 months are eligible Participants with known brain metastases should be excluded from this clinical trial Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases Uncontrolled brain or leptomeningeal metastases, including those who continue to require glucocorticoids for brain or leptomeningeal metastases Prior whole brain irradiation Patient with distant metastases Patients with rapidly advancing parenchymal brain metastases (Cohort D) Patient with treated (surgically excised or irradiated) and stable brain metastases are eligible as long as the treatment was at least 4 weeks prior to initiation of study drug and baseline brain computed tomography (CT) with contrast or magnetic resonance imaging (MRI) within 2 weeks of initiation of study drug is negative for new brain metastases. Subjects with stable brain metastases must not require therapy with corticosteroids Has CNS Disease: Participants with brain or subdural metastases are not eligible unless the metastases are asymptomatic and do not require treatment or have been adequately treated by local therapy (eg, surgery or radiotherapy) and have discontinued the use of corticosteroids for this indication for at least 4 weeks prior to study drug administration. Confirmation of radiographic stability must be done by comparing the brain scan (CT or MRI) performed during the Screening Period, using the same imaging modality, to a brain scan performed earlier (and following local therapy where applicable). Participants must be clinically stable. It is not the intention of this protocol to treat participants with active brain metastases. Note: CNS imaging is required to confirm eligibility for participants with a known history of CNS disease. Has known active central nervous system (CNS) metastases NOTE: Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging [using the identical imaging modality for each assessment, either magnetic resonance imaging (MRI) or computerized tomography (CT) scan] for at least four weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to study treatment; Evidence of symptomatic brain metastases. Patients with treated (surgically excised or irradiated) and stable brain metastases are eligible, assuming the patient has adequately recovered from treatment Patients with untreated brain metastases are excluded. However, patients with metastatic central nervous system (CNS) tumors may participate in this trial, if the patient is > 4 weeks from therapy completion (including [incl.] radiation and/or surgery), is clinically stable at the time of study entry and is receiving a stable or decreasing dose of corticosteroid therapy; brain magnetic resonance imaging (MRI) or head computed tomography (CT) is required at screening for patients with known brain metastases Symptomatic or history of untreated brain or leptomeningeal metastases; treated patients should be neurologically stable for 4 weeks after completion of appropriate therapy; patients should be off steroids at least 3 days prior to start of therapy on clinical trial Previously untreated brain metastases. Patients who have received radiation or surgery for brain metastases are eligible if therapy was completed at least 3 weeks previously and there is no evidence of central nervous system disease progression, mild neurologic symptoms, and no requirement for chronic corticosteroid therapy. Symptomatic brain metastases; asymptomatic brain metastases are allowed provided that they have been treated, have been stable for greater than (>) 6 weeks as documented by radiographic imaging, and do not require prolonged (>14 days) systemic corticosteroid therapy Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for 4 weeks or more after treatment is complete and within 28 days prior to the first dose of nivolumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration. Requirement of radiotherapy to treat brain metastases or receipt of any non-study systemic therapy for cancer or any other experimental/investigational treatment. Have symptomatic central nervous system metastases. Patients with brain metastases that have been previously treated and are stable for ? 4 weeks or treated with gamma knife surgery and are stable for ? 2 weeks are allowed to enter the study. Uncontrolled brain metastases or treatment by neurosurgical resection or brain biopsy within 4 weeks prior to Day 1. Brain metastases, which are symptomatic; patients with treated, brain metastases are eligible with stable brain disease for at least 4 weeks without the requirement for steroids or anti epileptic therapy Greater than 3 presumed melanoma brain metastases on contrast-enhanced brain MRI scan obtained no greater than 4 weeks prior to study registration Patients are excluded if they have been treated with whole brain radiotherapy within the prior 3 months. Participants with history of brain metastases or of leptomeningeal involvement should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events Patients with asymptomatic brain metastases that have been treated are eligible if the following criteria are met: No history of seizures in the preceding 6 months. Definitive treatment must have been completed >/= 4 weeks prior to registration. Subjects must be off steroids that were being administered because of brain metastases or related symptoms for >/= 2 weeks. Post-treatment imaging within 2 weeks of registration must demonstrate stability or regression of the brain metastases. Patients with brain metastases (except as allowed in section 4.1.14 of the protocol. Neurological assessment will be used to determine brain metastases. Patient with active brain metastases are not eligible. Patients with treated brain metastases are eligible if : presence of 3 brain lesions or less Known brain metastases (unless previously treated and well controlled for a period of > or = 3 months). Presence of brain metastases, unless the patient received brain irradiation, including adequate stereotactic radiosurgery, at least 4 weeks prior to randomization, and is stable, asymptomatic, and off steroids for at least 3 weeks prior to randomization Patients with known brain metastases may be included in the study, providing they are clinically stable. No evidence of distant metastases Previous radiotherapy to the brain. Known brain metastases Known symptomatic brain metastases requiring steroids. Clinically active known brain metastasis unless the brain metastases have been previously treated and are considered stable. Stable brain metastases are defined as no change on computed tomography (CT) scan or magnetic resonance imaging (MRI) for a minimum of 2 months and no change in steroid dose for a minimum of 4 weeks prior to starting the trial. Known malignant central nervous system (CNS) disease other than neurologically stable, treated brain metastases – defined as metastasis having no evidence of progression or hemorrhage for at least 2 weeks after treatment; must be off any systemic corticosteroids for the treatment of brain metastases for at least 14 days prior to enrolment Either no brain metastases or irradiated stable brain metastases Known central nervous system (CNS) disease, except for treated brain metastasis. Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, linear accelerator [LINAC], or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 will be excluded. Known brain metastases. Patients with known brain metastases must be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events Brain metastases unless treated with curative intent (gamma knife or surgical resection) and without evidence of progression for ? 2 months. Brain metastases. Note: Patients with a history of brain metastases may be eligible, if an imaging scan with contrast enhancement not older than 4 weeks is able to exclude the existence of currently active brain metastasis Patients with untreated, symptomatic brain metastases should be excluded from this clinical trial (patients with asymptomatic brain metastases amenable to treatment with Gamma Knife radiosurgery [“GKRS”] are eligible and may receive GKRS while on protocol) Evidence of leptomeningeal metastases Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis\r\n* (Dose level 1) subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment\r\n* (Dose Level 2 and 3) subjects may not have any history of or current CNS metastases; baseline imaging of the brain is required within 28 days prior to the start of study treatments Symptomatic brain metastases (if a patient has brain metastases and is on steroids, the steroid dose must have been stable for at least 14 days) or brain metastases that have not been previously treated Patients with active brain metastases or carcinomatous meningitis are excluded from this clinical trial; patients with treated brain metastases, whose brain metastatic disease has remained stable for >= 4 weeks without requiring steroid and anti-seizure medication are eligible to participate Patients with active brain metastases or carcinomatous meningitis are excluded from this clinical trial; patients with treated brain metastases, whose brain metastatic disease has remained stable for >= 4 weeks without requiring steroid and anti-seizure medication, are eligible to participate REGISTRATION TO TREATMENT (STEP 1): Patient must not have known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of protocol treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to protocol treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability REGISTRATION TO TREATMENT (STEP 2): Patient must not have known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of protocol treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to protocol treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Prior whole brain irradiation Known central nervous system (CNS) disease other than neurologically stable, treated brain metastases - defined as metastasis having no evidence of progression or hemorrhage for at least 2 weeks after treatment (including brain radiotherapy). Must be off any systemic corticosteroids for the treatment of brain metastases for at least 14 days prior to enrollment. Symptomatic central nervous system metastases; subjects with brain metastases that have been previously treated and are stable for 4 weeks off steroids are allowed; patients must be stable off steroids for brain metastases for at least 7 days; subjects with asymptomatic clinically insignificant brain metastases not requiring treatment are allowed; the exception does not include carcinomatosus meningitis which is excluded regardless of clinical stability Patients with any evidence of distant metastases Patients with known metastases would be excluded from this clinical trial Patients with previously untreated and or symptomatic brain metastases are excluded from this clinical trial Has untreated CNS metastases and/or carcinomatous meningitis that meets RECIST criteria identified either on the baseline brain imaging obtained during the screening period or identified prior to signing the informed consent form (ICF); patients whose brain metastases have been treated may participate provided they show radiographic stability (defined as 2 brain images, both of which are obtained after treatment to the brain metastases; these imaging scans should both be obtained at least four weeks apart and show no evidence of intracranial progression). In addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on a steroid dose of =< 10mg/day of prednisone or its equivalent and not requiring anticonvulsants for at least 14 days prior to the start of treatment Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided there is no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible In patients with central nervous system (CNS) metastases, metastases must be asymptomatic at the time of day 1 of the study and meet the following criteria: \r\n* Brain metastases should have been treated with either whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS)/gamma-knife, or surgical resection; \r\n* At least 28 days without progression of CNS metastases as evidenced by magnetic resonance imaging (MRI) or CT from last day of treatment with radiation to the CNS metastases; \r\n* At least 3 months from surgical resection (if had surgery) with stability on MRI brain at enrollment; \r\n* At least 14 days since last dose of corticosteroids; \r\n* Must not have leptomeningeal disease or cord compression Documented primary brain malignancy or brain metastases Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to trial registration and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial registration Prior whole brain irradiation. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to registration for protocol therapy and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior registration for protocol therapy; this exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability\r\n* NOTE: Subjects with neurological symptoms must undergo a head computed tomography (CT) scan or brain magnetic resonance imaging (MRI) to exclude brain metastasis Patients with treated brain metastases are eligible for study participation; patients may not receive ongoing treatment with steroids at screening; anticonvulsants (at stable dose) are allowed; treatment for brain metastases may be whole?brain radiotherapy, radiosurgery, neurosurgery, or a combination as deemed appropriate by the treating physician; radiotherapy and stereotactic radiosurgery must be completed at least 28 days prior to randomization Patients with known brain metastases should be excluded from this clinical trial Patients with a history of resected brain metastases are eligible only if they are asymptomatic and have stable MRI scans for 3 consecutive months, including =< 28 days of study registration Patients who receive stereotactic radiosurgery or whole brain radiation for brain metastases are eligible only if they are asymptomatic and have stable MRI scans for 3 consecutive months, including =< 28 days of study registration Known brain metastases (even if treated) Subjects with known symptomatic brain metastasis are not suitable for enrolment. Subjects with asymptomatic, stable, treated brain metastases are eligible for study entry. Participants with known brain metastases should be excluded from this clinical trial Known brain metastases or CNS cancer unless adequately treated with radiotherapy and/or surgery and stable for ? 2 mo Patients with active brain metastases or leptomeningeal metastases Active brain metastases Known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging =< 4 weeks prior to registration and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids =< 7 days prior to registration; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with known active or history of brain metastases should be excluded from this clinical trial Participants with known brain metastases should be excluded from this clinical trial Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with known brain metastases should be excluded from this clinical trial Patients are ineligible if they have any currently active central nervous system (CNS) metastases; patients who have treated brain metastases (with either surgical resection or stereotactic radiosurgery) that have been stable on head magnetic resonance imaging (MRI) or contrast computed tomography (CT) scan for at least 4 weeks following treatment and within 4 weeks prior to randomization are eligible; patients must not have taken any steroids =< 14 days prior to randomization for the purpose of managing their brain metastases; patients with only whole brain irradiation for treatment of CNS metastases will be ineligible Distant metastases Participants with previous brain metastases are eligible provided that they are treated and asymptomatic not requiring steroids or anticonvulsants, and have stable disease at the screening tumor assessment; a 4 week disease stable interval as confirmed by magnetic resonance imaging (MRI) or computed tomography (CT) brain w/ contrast is required after treatment of brain metastases before initiation of thoracic radiation therapy; in addition, subjects must have been either off corticosteroids, or on a stable or decreasing dose of 10 mg daily prednisone (or equivalent) Patients with known brain metastases Patients are excluded if they have active brain metastases or leptomeningeal metastases; subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for 14 days prior to initiation of treatment DOSE ESCALATION COHORT: Brain metastases: symptomatic, unstable, or disease requiring use of steroid treatment DOSE EXPANSION COHORT: Brain metastases: symptomatic, unstable, or disease requiring use of steroid treatment Patients with symptomatic uncontrolled brain metastases; a scan to confirm the absence of brain metastases is not required; the patient can receive a stable dose of corticosteroids before and during the study if these were started at least 4 weeks prior to treatment; patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days; patients with known uncontrolled brain metastases should be excluded from this clinical trial Patients are excluded if they have active, symptomatic brain metastases or leptomeningeal metastases; subjects with known brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for four weeks (after treatment is complete and within 28 days prior to study drug administration) Patients with brain metastases Subjects with treated brain metastases are eligible provided the metastases are clinically stable and greater than 8 weeks has elapsed from time of treatment and date of initiation of study drug Active central nervous system (CNS) metastases. Subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for (lowest minimum is 4 weeks or more) after treatment is complete and within 28 days prior to the first dose of nivolumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration. Patients with known brain metastases should be excluded from this clinical trial; no additional workup is needed to exclude brain metastases if the patient is asymptomatic or has no history of brain metastases Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids Untreated brain metastases Participants with known brain metastases should be excluded from this clinical trial Subjects with symptomatic brain metastases will be excluded from trial secondary to poor prognosis; however, subjects who have had treatment for their brain metastasis and whose brain disease is stable without steroid therapy for at least 3 months may be enrolled Patients with known brain metastases should be excluded from this clinical trial Patients with known brain metastases are excluded Patients with brain metastases are allowed provided that:\r\n* No leptomeningeal disease is present\r\n* Intracranial disease is controlled by prior local therapies (craniotomy, stereotactic radiosurgery, whole brain irradiation), as evidenced by brain MRI 4 weeks post treatment indicating no new intracranial disease\r\n* Stable or decreasing dose of steroids provided patient on =< 20 mg of prednisone or its equivalent daily Patients with untreated brain metastases, spinal cord compression, or evidence of symptomatic brain metastases or leptomeningeal disease as noted on computed tomography (CT) or magnetic resonance imaging (MRI) scans should not be included on this study, since neurologic dysfunction may confound the evaluation of neurologic and other adverse events; patients with treated brain metastases and resolution of any associated symptoms must demonstrate stable post-therapeutic imaging for at least 6 months following therapy prior to starting study drug Active brain metastasis or leptomeningeal disease; patients with known brain metastases are allowed if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 12 weeks after treatment is complete and within 28 days prior to the first dose of nivolumab administration; there must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration Has known active and untreated brain (central nervous system [CNS]) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate Patients with known brain metastases should be excluded from this clinical trial Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 3 months prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Known brain metastases, except brain metastases that have been previously removed or irradiated and currently have no clinical impact If history of brain metastases must be stable for at least 3 months after treatment-a brain computed tomography (CT) scan will only be required in subjects with known brain metastases at the time of enrollment or in subjects with clinical signs or symptoms suggestive of brain metastases Brain metastases per MRI or CT at any time prior to registration; NOTE: patients that have had primary therapy for brain metastasis (i.e. surgical resection, whole brain radiation, or stereotactic radiotherapy [SRT] even if stable) are not eligible Resection of brain metastases, otherwise untreated with radiation for those brain lesions (presenting for postoperative consolidative radiotherapy) Active brain metastases; patients with treated and stable (for at least 4 weeks) brain metastases are eligible; brain metastases will not be considered measurable lesions for the purpose of this trial Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with known brain metastases are excluded from this clinical trial, with the exception of patients whose brain metastatic disease status has remained stable for >= 2 months after treatment of the brain metastases, without steroids or anti-seizure medications; these patients may be enrolled at the discretion of the principal investigator Has known active CNS metastases and/or carcinomatous meningitis; participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability Extensive active brain disease including symptomatic brain metastases or presence of leptomeningeal disease \r\n* NOTE: Patients with brain metastasis, after definitive therapy with surgery or stereotactic radiation and stable off steroids for >= 4 weeks, are eligible Subjects with known brain metastases Patients with stable and controlled brain metastases for at least 3 months who also do not require steroids Primary brain tumors or active brain metastases Untreated brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases Patients with brain metastases (including treated or stable brain metastases) Patients with known brain metastases should be excluded from this clinical trial; previously treated brain metastases, neurologically stable, and no ongoing or anticipated need for steroid therapy are eligible Patients must not have active brain metastases from a systemic solid tumor Patients with known brain metastases should be excluded from early clinical trials Subjects with no brain metastases or a history of previously treated brain metastases who:\r\n* Have been treated by surgery or stereotactic radiosurgery (SRS) at least 4 weeks prior to enrollment\r\n* AND have a baseline magnetic resonance imaging (MRI) that shows no evidence of active intracranial disease\r\n* AND have not had treatment with steroids within 1 week of study enrollment\r\n* Neuroblastoma (NB): Concurrent use of steroids as a supportive medication, e.g. for appetite stimulation is allowed, but must comply with the doses listed Patients with untreated brain or meningeal metastases Known active brain metastases and or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided brain metastases are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to study registration; this exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Brain metastases from breast cancer with or without prior treatment; whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS) or surgical resection permitted through progression; progression must be documented in an at least one lesion untreated by SRS or in any site after surgery or WBRT History of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformations Subjects with previously treated brain metastases who are free of central nervous system (CNS) symptoms and are > 3 months from treatment of brain metastases are eligible Patients with known brain metastases or leptomeningeal metastases are excluded unless the following conditions are met:\r\n* Metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks after treatment is complete (must be confirmed within 28 days prior to the first dose of nivolumab administration) \r\n* There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration Patients with known brain metastases should be excluded from this clinical trial Patients with brain metastases may participate in this trial provided they are clinically stable; patients who are < 1 month from definitive therapy, receiving steroid therapy or taper, or anti-convulsant medications (started for brain metastases) must not be included Patients with up to 3 brain metastases (symptomatic and non-symptomatic) can be treated on this study; maximum diameter of each brain lesion should be =< 5 cm; maximum tumor volume =< 120 cc Patients who have previously been treated with whole brain radiation Patients with treated, stable, and asymptomatic brain metastases are eligible Untreated, progressing, or symptomatic brain metastases Untreated brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases Patients with known brain metastases should be excluded from this clinical trial Extensive active brain disease including symptomatic brain metastases or presence of leptomeningeal disease Evidence of leptomeningeal metastases History of another malignancy that makes determination of the source of the brain metastases uncertain Patients with known active brain metastases or carcinomatous meningitis are excluded from this clinical trial; patients whose brain metastatic disease status has remained stable for >= 4 weeks following treatment of brain metastases are eligible to participate at the discretion of the principal investigator Extensive active brain disease, including symptomatic brain metastases or the presence of leptomeningeal disease\r\n* Patients with brain metastasis, after definitive therapy with surgery or stereotactic radiation and stable off steroids for > 4 weeks, are eligible Brain metastases that are symptomatic or requiring corticosteroids (except inhaled); subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks Study participants with brain metastases are excluded unless these have been definitively treated and are radiographically stable for at least 1 month; the study participant must also demonstrate a stable physical exam and must have discontinued systemic steroids for treatment of edema related to brain metastases or treatment for over 7 days Distant metastases Patients with known brain metastases should be excluded from this clinical trial Untreated brain metastases (or local treatment of brain metastases within the last 6 months) No active brain metastases or epidural disease; patients with brain metastases previously treated with whole brain radiation or radiosurgery or patients with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 12 weeks before starting study treatment; baseline brain imaging with contrast-enhanced CT or MRI scans for patients with known brain metastases is required to confirm eligibility Brain metastases or a history of brain metastases Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible; patients with surgically resected brain metastases are eligible Patients who have had brain metastases will be eligible only if all of the following are true:\r\n* The total number of brain metastases ever is =< 3\r\n* All are less than or equal to 2 cm\r\n* They have been resected surgically or have been treated with gamma-knife or stereotactic radiosurgery\r\n* The patient has not taken any steroids =< 30 days prior to registration for the purpose of managing their brain metastases At least one measurable lesion in the brain (>= 10 mm on T1-weighted, gadolinium-enhanced magnetic resonance imaging [MRI]); (prior neurosurgical resection, whole brain radiation or stereotactic radiation therapy is allowed provided the patient has a measurable CNS progression [at least one new and/or progressive measurable brain metastasis]; measurable or non-measurable extracranial metastases allowed); if the potential participant has received brain radiation there needs to be at least one new and/or progressive measurable brain metastases after radiation is completed; do not consent patients if you are planning on administering brain radiation therapy Prior radiation for bone or brain metastases is permitted if patient is now asymptomatic and has completed all radiation and steroid therapy (if applicable) for brain or bone metastases >= 2 weeks prior to study enrollment Symptomatic brain or bone metastases; prior radiation and/or steroid therapy for brain or bone metastases (if applicable) must be completed >= 2 weeks prior to study enrollment Patients with known brain metastases Subjects with untreated or uncontrolled brain metastases or evidence of leptomeningeal disease; brain metastases that have been appropriately treated with radiation and/or surgery will be allowed as long as the central nervous system (CNS) disease has been stable for at least 4 weeks post-treatment Patients with symptomatic brain metastases are excluded from this study Visceral metastases (e.g. lung, liver, brain, kidney, spleen) Subjects with known brain metastases Patients with known distant metastases Patients with known brain metastases Patients with untreated symptomatic brain metastases are excluded; however, patients with metastatic central nervous system (CNS) tumors may participate in this trial, if the patient is > 4 weeks from therapy completion (including radiation and/or surgery), is clinically stable at the time of study entry and is not receiving corticosteroid therapy for the brain metastases (mets) Patients with known brain metastases may be enrolled if this site of disease has been adequately treated, the patient does not require steroids, and the patient has been stable for at least 3 months prior to enrollment Patients with a history of brain metastases are eligible if they have been treated with radiation and have stable brain metastases at least 3 months after radiation and must also be off steroids Patients with known brain metastases with active symptoms or requiring anticonvulsive medications, or steroids should be excluded from this clinical trial Patients with brain lesions that have been treated with whole brain radiotherapy and are clinically stable for at least 4 weeks, are not taking steroids and are not receiving enzyme-inducing anticonvulsants will be eligible Patients with symptomatic brain metastases who have not completed radiation therapy and/or are receiving systemic steroid therapy; patients with leptomeningeal disease will be excluded Prior treated brain or meningeal metastases must be without magnetic resonance imaging (MRI) evidence of progression for at least 8 weeks and off immunosuppressive doses of systemic steroids (> 10 mg/day prednisone or equivalent) for at least 2 weeks before study drug administration\r\n* For the current amendment 7, up to ten patients may be included in cohort 6 that have four or fewer untreated brain metastases, with no lesion larger than 2 cm, and no evidence of cerebral edema requiring steroids Patients with resected or radiated brain metastases or those treated with stereotactic radiation therapy are eligible, provided they have been off steroids for at least 2 weeks; no history of stroke within the past 6 months Documented evidence of distant metastases Subjects with brain metastases as their first site of disease recurrence may be eligible if treated by definitive radiation (stereotactic radiosurgery or whole brain) with clinically controlled neurologic symptoms for a period of 21 days prior to study treatment Participants with known brain metastases should be excluded from this clinical trial Patients must have a CT or MRI scan of the brain to evaluate for central nervous system (CNS) disease within 42 days prior to registration; patient must not have symptomatic brain metastases or evidence of leptomeningeal carcinomatosis; patients with asymptomatic brain metastases are eligible if off of steroids for at least 7 days prior to registration without development of symptoms Histologically confirmed malignant melanoma with measurable metastases in the brain. Both asymptomatic and symptomatic patients. Patients with known brain metastases are not eligible; brain imaging studies are not required for eligibility if the patient has no neurologic signs or symptoms suggestive of brain metastasis; but, if brain imaging studies are performed, they must be negative for disease Symptomatic or uncontrolled brain metastases; NSCLC subjects with known brain metastases (certain exceptions allowed) Gastric adenocarcinoma subjects with brain metastases The participant has documented brain metastases or leptomeningeal disease. Active brain metastases or leptomeningeal metastases are not allowed. Confirmed brain and/or leptomeningeal metastases Evidence of active brain metastases, including leptomeningeal involvement (prior evidence of brain metastasis are permitted only if treated and stable and off therapy for ? 4 weeks prior to first dose of study drug). Patients with known symptomatic brain metastases requiring steroids. Untreated brain metastasis(es) that may be considered active. Patients with previously treated brain metastases may participate provided they are stable (i.e., without evidence of progression by imaging for at least 6 weeks prior to the first dose of study treatment, and any neurologic symptoms have returned to baseline), and there is no evidence of new or enlarging brain metastases, and the patient does not require any systemic corticosteroids for management of brain metastases within 4 weeks prior to the first dose of REGN2810 (certain exceptions may apply). Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable. Exception: Adequately treated brain metastases documented by baseline CT or MRI scan that has not progressed since previous scans and that does not require corticosteroids (except prednisone ? 5 mg/day or equivalent) for management of CNS symptoms. A repeat CT or MRI following the identification of CNS metastases (obtained at least 2 weeks after definitive therapy) must document adequately treated brain metastases. Active brain metastases or carcinomatous meningitis (treated metastases are permitted, provided the patient is asymptomatic and off steroids for 28 days) Evidence of distant metastases Patients with known active brain or central nervous system metastases, including leptomeningeal disease; patients with treated and asymptomatic brain metastases may be eligible after discussion with PI Known active central nervous system (CNS) metastases and/or carcinomatous meningitis Note: Patients previously treated for brain metastases may be able to participate provided they are stable All subjects with brain metastases, except those meeting the following criteria: a. Brain metastases have been treated locally, have not been progressing at least 2 months after completion of therapy, and no steroid maintenance therapy is required, and b. No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable) Known active brain metastases and/or carcinomatous meningitis Progression of or new brain metastases after completion of whole-brain radiotherapy or stereotactic radiosurgery Patients must not have symptomatic uncontrolled brain or leptomeningeal metastases. Active brain metastases or leptomeningeal metastases Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery and stable for at least 3 months before randomization. Known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, have discontinued corticosteroid treatment for these metastases for at least 4 weeks prior to study entry and are neurologically stable. Brain metastases considered unstable as: Participants with a history or clinical evidence of central nervous system primary tumors or metastases including leptomeningeal metastases unless they have been previously treated, are asymptomatic, and have had no requirement for steroids or enzyme-inducing anticonvulsants in the last 14 days before screening Patients with known brain metastases should be excluded from this clinical trial Known brain metastases, unless stable or previously treated. Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided:\r\n* The brain metastases have been treated\r\n* The patient is asymptomatic from the brain metastases at enrollment\r\n* Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration\r\n* The brain metastases are stable on pre-registration imaging Known brain metastases Presence of or known history of brain/CNS tumor or metastases Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms; participants with a history of treated central nervous system (CNS) metastases are eligible; treated brain metastases are defined as those having no evidence of progression for >= 1 month after treatment, and no ongoing requirement for corticosteroids, as ascertained by clinical examination and brain imaging (magnetic resonance imaging or computed tomography [CT] scan) completed during screening; any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 2 weeks prior to registration; treatment for brain metastases may include whole brain radiotherapy, radiosurgery, surgery or a combination as deemed appropriate by the treating physician Known brain metastases or CNS cancer unless adequately treated with radiotherapy and/or surgery and stable by symptoms and radiographic imaging and not requiring corticosteroids for at least 2 mo before randomization Patients with brain metastases are ineligible; all patients must have a pretreatment CT or MRI scan of the brain to evaluate for central nervous system (CNS) disease within 42 days prior to registration Participants with known brain metastases who have completed whole brain radiotherapy, stereotactic radiosurgery, or complete surgical resection will be eligible if they have remained clinically stable, asymptomatic, and off steroids for 1 month prior to enrollment. History of brain metastases that meet certain conditions; Brain metastases considered unstable as: Patients with clinically or radiologically unstable brain metastases are excluded from this clinical trial\r\n* Note: patients with stable brain metastases after treatment, for at least 3 months prior to enrolling on this trial, could participate in the study; patients should be off, or on a stable dose of steroids Have known brain metastases. Untreated or symptomatic brain metastases Symptomatic or progressive brain metastases. Evidence of distant metastases (M1) Patients must not have history of brain metastases At least one measurable BM by RECIST 1.1 criteria (? 10mm in longest diameter). Target lesions must not have received stereotactic radiotherapy (SRS). If subject had prior whole brain radiotherapy (WBRT), progression in any measurable BM lesion must have occurred at least 3 months after the end of WBRT. Subjects with asymptomatic brain metastases may be enrolled without prior radiation therapy to the brain. Subjects with minimally symptomatic brain metastases may be enrolled without prior radiation therapy to the brain if they do not require immediate surgical or radiation therapy in the opinion of the treating investigator and in the opinion of a radiation therapy or neurosurgical consultant Non-malignant neurological disease that would interfere with evaluation of symptoms or signs of brain metastases Untreated brain metastases Untreated or symptomatic brain metastases No known brain metastases Subjects with known or history of brain metastases or leptomeningeal disease: subjects with neurological symptoms must undergo a contrast CT scan or MRI of the brain within 28 days prior to randomization to exclude active brain metastasis. Imaging of the central nervous system (CNS) is otherwise not required. Patients with symptomatic brain metastases are excluded from this clinical trial Patients with known active brain metastases should be excluded from this clinical trial; patients with prior treated brain metastases are allowed, providing that they were not accompanied by seizures and that a baseline brain magnetic resonance imaging (MRI) scan prior to study entry demonstrates no current evidence of brain metastases; all patients with central nervous system (CNS) metastases must be stable for > 3 months after treatment and off steroid treatment prior to study enrollment Active brain metastases or leptomeningeal metastases Known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Brain metastases, unless previously treated and asymptomatic and not progressive for 2 months. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Note: Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging using the identical imaging modality for each assessment, either MRI or CT scan, for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. Symptomatic brain or meningeal tumors. Known central nervous system (CNS) metastases other than stable, treated brain metastases. Subjects with previously treated brain metastasis will be allowed if the brain metastasis has been stable by neuroimaging without steroid treatment for at least 3 months following prior treatment (radiotherapy or surgery). Subject has active brain metastases or leptomeningeal metastases. Subjects with prior history of brain metastasis who have undergone local therapy (i.e., metastasectomy and/or radiation) and show no evidence of local recurrence or progression over the past 3 months prior to Screening are eligible. Presence of symptomatic brain metastases requiring immediate treatment with radiation therapy or steroids. Known brain metastases Have known brain metastases. Any known untreated brain metastases. Treated subjects must be stable 4 weeks after completion of treatment for brain metastases and image documented stability is required. Patients must have no clinical symptoms from brain metastases and must be either off of steroids or on a stable dose of steroids for at least 2 weeks prior to protocol enrollment. Patients with known leptomeningeal metastases are excluded, even if treated Presence of brain metastases Cancer metastases in the brain Subjects with brain metastases (subjects must have a CT scan or MRI of the head within 28 days prior to enrollment to rule out brain metastases), uncontrolled seizure disorder, or active neurologic disease Any brain metastases including leptomeningeal metastases, are excluded, even if treated and stable. Patients with known brain metastases should be excluded from this clinical trial Subject has known history of brain metastases unless previously treated and well controlled for at least 3 months (defined as stable clinically, no edema, no steroids) Patients with known brain metastases History of brain or other CNS metastases. Patients with uncontrolled brain metastases; patients with brain metastasis must be asymptomatic and off corticosteroid use for at least one week Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, ie, without evidence of progression for at least 4 weeks by repeat imaging. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, ie, without evidence of progression for at least 4 weeks by repeat imaging, clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment. Patients are excluded if they have active brain metastases or leptomeningeal metastases; subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for (lowest minimum is 4 weeks or more) after treatment is complete and within 28 days prior to the first dose of nivolumab administration; there must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration New or progressive brain or meningeal or spinal metastases Subjects with active brain metastases or leptomeningeal metastases Participants with known leptomeningeal metastases or untreated brain metastases. Participants with known brain metastases will be eligible if they have completed the primary brain therapy (such as whole brain radiotherapy, stereotactic radiosurgery, or complete surgical resection) and if they have remained clinically stable, asymptomatic, and off steroids for at least 28 days. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they have stable brain metastases Known active central nervous metastases; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids > 10 mg/day pf prednisone or equivalent Patients with untreated brain metastases Documented or symptomatic brain metastases and/or central nervous system metastases or leptomeningeal disease Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Any known, untreated, brain metastases. Treated subjects must be stable 4 weeks after completion of treatment for brain metastases and image documented stability is required. Patients must have no clinical symptoms from brain metastases and have not required systemic corticosteroids >10 mg/day prednisone or equivalent for at least 2 weeks prior to first dose of study drug. Known brain or leptomeningeal disease (CT or MRI scan of the brain required only in case of clinical suspicion of central nervous system involvement). Presence of brain or subdural metastases Any signs and/or symptoms of brain metastases must be stable for ? 4 weeks Symptomatic central nervous system metastases; subjects with brain metastases that have been previously treated with whole body radiation therapy (WBXRT) and are stable for 6 weeks are allowed; (gamma or cyber knife treated lesions may enroll 2 weeks after completion if toxicities are resolved and no longer requiring steroids, patients with asymptomatic brain metastases are allowed after discussion with the study sponsor) Primary brain malignant tumors Known metastases to the brain Patients with symptomatic brain metastases. Documented brain metastases Subject has known brain metastases Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment No symptomatic, untreated, or uncontrolled brain metastases present Patients with known brain metastases are excluded from this clinical trial; patients with primary brain tumors amenable to surgery are allowed on this protocol Known brain metastases Patients with known or suspected leptomeningeal metastases. INCLUSION CRITERIA:\n\n - Age ? 18 years\n\n - Histologically confirmed diagnosis of unresectable stage III or metastatic melanoma\n (stage IIIC to IV per American Joint Committee on Cancer [AJCC])\n\n - Documented evidence of BRAF V600 mutation.\n\n - Newly obtained tumor biopsy at baseline, and patient agrees to a mandatory biopsy at\n the time of progression, if not medically contraindicated.\n\n - Evidence of measurable disease, as determined by RECIST v1.1.\n\n INCLUSION CRITERIA for triple combinations:\n\n Progressive disease following prior treatment with LGX818/MEK162 combination. PRINCIPAL\n EXCLUSION CRITERIA Symptomatic or untreated leptomeningeal disease.\n\n - Symptomatic brain metastases. Patients previously treated or untreated for brain\n metastases that are asymptomatic in the absence of corticosteroid therapy or on a\n stable dose of steroids for four weeks are allowed to enroll. Brain metastases must be\n stable at least 4 weeks with verification by imaging (e.g. brain MRI completed at\n screening demonstrating no current evidence of progressive brain metastases). Patients\n are not permitted to receive enzyme inducing anti-epileptic drugs.\n\n - Patients who have developed brain metastases during Part I of the study may continue\n to Part II upon discussion with Novartis Medical Monitor. The brain metastasis must be\n either asymptomatic or treated and stable for at least 4 weeks and on a stable or\n tapering dose of steroids for at least 2 weeks. Patients with brain metastasis are not\n eligible for the combination with LEE011.\n\n - Known acute or chronic pancreatitis.\n\n - History or current evidence of retinal vein occlusion (RVO) or current risk factors\n for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity\n or hypercoagulability syndromes);\n\n - Clinically significant cardiac disease including any of the following:\n\n - CHF requiring treatment (NYH grade ? 2),\n\n - LVEF < 50% as determined by MUGA scan or ECHO\n\n - History or presence of clinically significant ventricular arrhythmias or atrial\n fibrillation\n\n - Clinically significant resting bradycardia\n\n - Unstable angina pectoris ? 3 months prior to starting study drug\n\n - Acute Myocardial Infarction (AMI) ? 3 months prior to starting study drug,\n\n - QTcF > 480 msec. Patients with any of the following laboratory values at\n\n Screening/baseline:\n\n - Absolute neutrophil count (ANC) <1,500/mm3 [1.5 x 109/L]\n\n - Platelets < 100,000/mm3 [100 x 109/L]\n\n - Hemoglobin < 9.0 g/dL\n\n - Serum creatinine >1.5 x ULN or calculated or directly measured CrCl < 50% LLN (lower\n limit of normal)\n\n - Serum total bilirubin >1.5 x ULN\n\n - AST/SGOT or ALT/SGPT > 2.5 x ULN, or > 5 x ULN if liver metastases are present\n\n Additional exclusion criteria for the triple combinations:\n\n LGX818/MEK162/BKM120:\n\n - Patients with fasting glucose > 120 mg/dL or 6.7 mmol/L, and HbA1c > 8 %.\n\n - Patient has any of the following mood disorders as judged by the\n\n Investigator or a Psychiatrist:\n\n - Patient has a score ? 12 on the PHQ-9 questionnaire\n\n - Patient has ? CTCAE grade 3 anxiety\n\n LGX818/MEK162/BGJ398:\n\n - History and/or current evidence of significant ectopic mineralization/ calcification\n with the exception of calcified lymph nodes and asymptomatic vascular calcification.\n\n - Current evidence of corneal disorder/ keratopathy incl. but not limited to bullous/\n band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjunctivits etc.,\n confirmed by ophthalmologic examination\n\n LGX818/MEK162/LEE011:\n\n - Patients with uncontrolled hypertension (please refer to WHO-ISHguidelines) are\n excluded from study.\n\n - QTcF >450 ms for males and >470 ms for females Congenital long QT syndrome or family\n history of unexpected sudden cardiac death and/or hypokalemia CTCAE Grade ? 3 and\n magnesium levels below the clinically relevant lower limits at study entry\n\n - Current evidence of brain metastasis or brain metastasis detected by mandatory CT/MRI\n at screening\n\n - PT/INR or aPTT > 1.5xULN\n\n Other protocol-defined inclusion/exclusion criteria may apply. Active brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases; treated, asymptomatic metastases are permitted provided the patient has been off steroids for at least 1 month prior to day 1 of study drug Presence of distant metastases Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed incidentally at study baseline) Known clinically active brain metastases; prior evidence of brain metastasis successfully treated with surgery or radiation therapy will not be exclusion for participation as long as they are deemed under control at the time of study enrollment and there are no neurological signs of potential brain metastases Known untreated brain metastases Active brain metastases (e.g. stable for < 4 weeks) Symptomatic uncontrolled brain metastases Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events Patients with known metastases are not eligible Patient has evidence of distant metastases Any history of or current brain or subdural metastases Patients with known brain metastases should be excluded from this clinical trial The subject has active brain metastases, leptomeningeal or epidural disease (Note: subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain scans are not required to confirm eligibility) Patients with untreated brain metastases should be excluded from this clinical trial Brain metastases unless resected or irradiated and stable >= 4 weeks Subject has known or suspected primary brain or leptomeningeal metastases Patients must not have known brain metastases because the study drug has not been adequately tested in this setting Clinically active brain metastases; radiological documentation of absence of active brain metastases at screening is required for all patients; prior evidence of brain metastasis successfully treated with surgery or radiation therapy will not be exclusion for participation as long as they are deemed under control at the time of study enrollment Have active brain metastases. Subjects with brain metastases are allowed if they completed definitive brain therapy, are asymptomatic and radiologically stable, and if they are not currently receiving corticosteroids or radiation. Subject has known symptomatic brain metastases or leptomeningeal involvement as assessed by CT scan or MRI. Subjects with stable asymptomatic brain metastases or leptomeningeal disease are eligible if they have not required new treatments for this disease in a 28 day period before the first dose of study drug, and anticonvulsants and steroids have not been administered for a period of 2 weeks prior to the first dose of study drug. Active brain metastases (defined as neurologically stable for less than (<) 4 weeks and/or symptomatic and/or requiring treatment with steroids and/or leptomeningeal disease) Subjects must have completed any prior treatment for brain metastases >= 4 weeks prior to start of therapy (>= 2 weeks for stereotactic radiosurgery/gamma knife). Subjects who are neurologically stable on symptomatic therapy with anticonvulsants with low drug interaction risk or whose steroids are being tapered are eligible. Asymptomatic untreated brain metastases less than or equal to (<=) 1 cm of longest diameter are eligible Known active central nervous system (CNS) metastases and/or carcinomatous meningitis; patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability Patients with primary brain tumors are excluded. Patients with known progressive brain metastases determined by serial imaging or declining neurologic function in the opinion of the treating physician are not eligible. Patients with previously treated brain metastases are eligible, provided that the patient has not experienced a seizure or had a clinically significant change in neurological status within the 3 months prior to registration. All patients with previously treated brain metastases must be clinically stable for at least 1 month after completion of treatment and off steroid treatment for one month prior to study enrollment. Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Presence of symptomatic brain metastases requiring immediate treatment with radiation therapy or steroids. Brain metastases: brain metastases must have been treated at least 2 weeks prior to enrollment, be asymptomatic from brain metastases, stable on brain imaging, and not be receiving a supra-physiologic dose of steroids (> 10 mg prednisone daily or equivalent). Patients with known brain metastases should be excluded from this clinical trial Subjects with treated brain metastases must have been treated with surgery and/or radiation therapy ? 21 days pre-study and must be clinically stable. Patients are excluded if they have active brain metastases or leptomeningeal metastases; subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 6 months after treatment is complete and within 28 days prior to the first dose of nivolumab and bevacizumab administration; there must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration Brain metastases or history of leptomeningeal carcinomatosis Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include clinically active and significant carcinomatous meningitis which is excluded regardless of clinical stability Participants with symptomatic or growing brain metastases less than 4 weeks prior to enrollment. Patients with stable brain metastases will be allowed provided the following criteria are met:\r\n* Brain radiation was already provided at least 4 weeks prior to initiating study treatment\r\n* The subject has no new or progressive neurologic symptoms AND neurological symptom stability for the last 4 weeks prior to the study\r\n* The subject has been off of corticosteroids for at least 7 days prior to trial treatment\r\n* The subject does not have carcinomatous meningitis Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain parenchymal metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the 1st dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Patients with known brain metastases are NOT eligible for participation unless the brain metastases are treated (either with surgical excision, stereotactic radiosurgery or radiotherapy) and have been stable based on the physician’s assessment, the patient is asymptomatic and has discontinued corticosteroids if taken for that purpose Subjects who have new or progressive brain or meningeal or spinal metastases. Untreated brain metastases. Participants must have completed treatment for brain metastasis, and be neurologically stable off steroids, for at least 28 days prior to first dose of study drug Brain metastases, meningeal tumours or other metastases in the central nervous system Patients with primary brain tumors are excluded; patients with metastatic brain tumors may be enrolled Has known brain metastases Known leptomeningeal metastases not amenable to radiotherapy; patients receiving radiotherapy for leptomeningeal metastases are eligible Brain metastases, leptomeningeal disease or bone metastases The subject has active brain metastases or epidural disease (Note: Subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible) Presence of symptomatic brain metastases requiring immediate treatment with radiation therapy or steroids. Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; patients with previously treated brain metastases may participate provided they are clinically stable without the use of systemic steroids for at least 8 weeks prior to study entry Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment The participant has brain metastases that are symptomatic. Untreated or progressive brain metastases; patients with treated brain metastases not requiring chronic corticosteroids for symptom control are eligible Participants with known uncontrolled brain metastases will be excluded from this clinical Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment There is no limit on the number of brain metastases Known leptomeningeal metastases The subject has active brain metastases or epidural disease (Note: subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; (baseline brain imaging with contrast-enhanced CT or magnetic resonance imaging [MRI] scans for subjects with known brain metastases is required to confirm eligibility) Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Known central nervous system (CNS) disease, except for treated brain metastasis; treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT]) during the screening period; anticonvulsants (stable dose) are allowed; treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, linear accelerator [LINAC], or equivalent) or a combination as deemed appropriate by the treating physician; patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 will be excluded Symptomatic metastatic brain or meningeal tumors; treated and stable, asymptomatic brain metastases, as long as treatment was greater than 4 weeks prior to informed consent, are allowed Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to trial registration and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial registration. Participants with known brain metastases Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Symptomatic central nervous system metastases; subjects with brain metastases that have been previously treated and are stable for 4 weeks are allowed Symptomatic brain metastases; known brain metastases are allowed if asymptomatic and previously treated Known brain metastases Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to study registration. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability. Patients with untreated brain metastases, spinal cord compression, or evidence of symptomatic brain metastases or leptomeningeal disease as noted on computed tomography (CT) or magnetic resonance imaging (MRI) scans are ineligible; screening imaging to rule out brain metastases is not required for screening, but should be performed prior to study enrollment if clinically indicated; patients with treated brain metastases must demonstrate stable post-therapeutic imaging and resolution of any associated symptoms and must be stably off steroids with no symptoms for at least 6 months following therapy prior to starting study drug Active central nervous system (CNS) metastases. Subjects must undergo a head computed tomography (CT) scan or brain MRI within 28 days prior to registration for protocol therapy to exclude brain metastases if symptomatic or without prior brain imaging Known brain metastases or leptomeningeal metastases; NOTE: symptomatic, and/or if they require immunosuppressive doses of corticosteroids (e.g. > 10 mg/day prednisone or equivalents) for at least 2 weeks prior to study drug administration; patients with treated brain metastases who are deemed clinically stable and without radiological progression on positron emission tomography (PET), MRI or computed tomography (CT) scan performed =< 8 weeks of study entry, are not excluded; NOTE: primary nasopharyngeal cancers that directly invade the skull base and extend into the infratemporal fossa (e) are not regarded as brain metastases and are not excluded Patients with asymptomatic brain metastases are allowed, as long as they are stable and do not require treatment with anticonvulsants or escalating doses of steroids; maximum daily dose of steroids should be prednisone 20 mg or equivalent; radiation therapy for brain metastases must be completed at least 14 days prior to treatment on protocol Patients with known brain metastases should be excluded from this clinical trial Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the radiation therapy and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to radiation treatment Has known brain metastases and/or carcinomatous meningitis Known brain metastases Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless or clinical stability Distant metastatic disease, including known brain metastases Uncontrolled central nervous system (CNS) metastases, including leptomeningeal metastases, are not allowed; subjects with previously treated brain metastases will be allowed if the brain metastases have been stable without steroid treatment for at least 4 weeks following prior treatment (radiotherapy or surgery) Any evidence of distant metastases (M1) Patients with history or evidence upon physical examination of central nervous system (CNS) disease, including primary brain tumor, seizures which are not controlled, any brain metastases and/or epidural disease, or history of cerebrovascular accident (CVA, stroke) within six months prior to the first date of study treatment Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis\r\n* Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Untreated or progressive brain metastases Known brain metastases Patient has a known history or evidence of brain metastases Brain metastases or leptomeningeal disease One or more brain metastases Prior radiation therapy to the brain is allowed with the exception of whole brain irradiation Previous whole brain radiotherapy Participants with known brain metastases will be excluded from this clinical trial Patients with known brain metastases should be excluded from this clinical trial Patients who had treatment for their brain metastases greater than 1 month prior to treatment will be eligible; any brain metastases must be stable and not progressing prior to study entry Patients with known brain metastases should be excluded from this clinical trial Participants with known brain metastases should be excluded from this clinical trial Previously untreated brain metastases. Patients with known brain metastases should be excluded from this clinical trial Known brain metastases Patients with known brain metastases Active brain metastases or leptomeningeal metastases are not allowed Subjects with a history of brain metastasis are eligible for the study as long as they meet all the following criteria: their brain metastases have been treated, they have no evidence of progression or hemorrhage after treatment, have been off dexamethasone for 4 weeks prior to first study drug administration, and have no ongoing requirement for dexamethasone or anti-epileptic drugs; Symptoms or signs of active brain metastases; Patients with untreated or progressing brain metastases Known brain metastases; Patients with known brain metastases should be excluded from this clinical trial Patients with known brain metastases; patients with neurological symptoms must undergo a computed tomography (CT) scan/magnetic resonance imaging (MRI) of the brain to exclude brain metastases Patients with known brain metastases will be eligible as long as they have completed radiation to the brain and have been off of corticosteroid therapy for at least 2 weeks prior to study treatment Patients with either untreated brain metastases or brain metastases treated within the past three months are ineligible PHASE I: Participants with untreated or uncontrolled brain metastases are excluded from this clinical trial; patients with treated and stable (> 4 weeks) brain metastasis are allowed PHASE II: Participants with known brain metastases should be excluded The subject has active brain metastases or epidural disease (Note: Subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible); neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment (Baseline brain imaging with contrast-enhanced CT or magnetic resonance imaging [MRI] scans for subjects with known brain metastases is required to confirm eligibility) Any known untreated brain metastases. Treated subjects must be stable for 4 weeks after completion of that treatment, with image documentation required. Patients must have no clinical symptoms from brain metastases and must be either off steroids or on a stable dose of steroids for at least 2 weeks prior to protocol enrollment. Patients with known leptomeningeal metastases are excluded, even if treated. Participants with symptomatic brain metastases that require chronic steroids are excluded; patients with a history of brain metastases are permitted to enroll as long as they have been treated, off of steroids and have been stable for one month on imaging Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases Untreated and/or uncontrolled brain metastases. At the time of day 1 of the study, subjects with brain metastases must be asymptomatic for at least 4 weeks and: at least 3 weeks without new brain metastases as evidenced by MRI/CT Untreated brain metastases (or local treatment of brain metastases within the last 6 months) Expansion A:\r\n* Brain metastases or leptomeningeal not previously treated with radiation or surgery Symptomatic brain metastasis or leptomeningeal disease requiring radiation therapy or escalating doses of steroids; patients with clinically stable brain metastases (previously treated or untreated) are eligible; patients in expansion cohort A must have at least one untreated central nervous system (CNS) lesion Participants with known brain metastases Individuals with symptomatic or progressive brain metastases are ineligible; subjects with treated brain metastases are eligible if they have no radiographic or other signs of progression in the brain for >= 3 weeks after completion of local therapy; any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 3 weeks prior to study enrollment Symptomatic brain metastases or brain metastases requiring chronic steroids to control symptoms. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression; should participants develop brain metastases while on trial and have clinical benefit from GSK1120212 and GSK2141795 otherwise, participants may continue on drug after clinical management of the brain metastases with the permission of the principal investigator; GSK1120212 and GSK2141795 should be restarted between 2 and 6 weeks after the last radiation treatment Brain metastases requiring steroids Patients with uncontrolled brain metastases; patients with brain metastases must have stable neurologic status following local therapy (surgery or radiation) for at least 2 weeks without the use of steroids or on stable or decreasing dose of =< 10 mg daily prednisone (or equivalent), and must be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; patients with a history of carcinomatous meningitis are not eligible Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 1 week prior to trial treatment; this is not applicable to patients with primary brain tumors Patients with known brain metastases or carcinomatous meningitis are excluded from this clinical trial, with the exception of patients whose brain metastatic disease status has remained stable for >= 2 months after treatment of the brain metastases; patients should be on stable doses of anti-seizure medications; these patients may be enrolled at the discretion of the principal investigator Untreated brain metastases. Absence of brain metastases is not required. Patients must not have symptomatic brain metastatic disease. The patient may be symptomatically controlled on a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment. Patients with known brain metastases requiring steroids. Participants with symptomatic or progressive brain metastases, or requiring steroids to control symptoms of brain metastases No known or suspected brain metastases (NOTE: patients with treated epidural disease are allowed) Known brain metastasis; participants with brain metastasis can only be included if they were treated > 4 week prior to enrollment with radiation and the effects of treatment have resolved; subjects with treated brain metastases must have a post-treatment brain magnetic resonance imaging (MRI) showing no further progression of prior lesions and no new metastatic lesions; subjects will be ineligible if they have any ongoing symptoms from brain metastases or if there continues to be radiographic evidence of cerebral edema Active brain metastases: participants with previously diagnosed brain metastases are eligible if they have completed treatment at least one month prior to enrollment, are neurologically stable, and have recovery from effects of radiotherapy or surgery All patients must undergo a CT or MRI of the brain within 42 days prior to registration; patients with asymptomatic brain metastases or previously treated brain metastases that are stable (i.e. not requiring corticosteroids) at the time of registration will be eligible Diagnosis of primary brain tumor or symptomatic brain metastasis. Patients with brain metastases must be without neurologic dysfunction that would confound the evaluation of neurologic and other AEs Patients must have radiographically-confirmed recurrent brain metastases from a solid tumor after WBRT Patients with treated brain metastases that have been stable for 1 month are eligible; patients must be off steroids for week prior to starting study treatment Participants with known brain metastases Subjects with known brain metastases who have completed whole brain radiotherapy, stereotactic radiosurgery, or complete surgical resection will be eligible if they have remained clinically stable, asymptomatic and off of steroids for 28 days. Leptomeningeal metastases or brain metastases except as for Inclusion Criterion #6. Patients will be excluded if they have had prior surgical resection of brain for other brain tumors Participants with known and untreated brain metastases are excluded; note: patients without known prior central nervous system (CNS) metastases and without clinical signs and symptoms of CNS involvement are not required to have a magnetic resonance imaging (MRI) of the brain prior to enrollment; patients with treated brain metastases that are asymptomatic and clinically stable for two weeks will be eligible for protocol participation Patients with known brain metastases will be excluded from this clinical trial Uncontrolled or symptomatic brain metastases that are not stable or require steroids, are potentially life-threatening or have required radiation within 28 days prior to first dose of study treatment. Active brain metastases or leptomeningeal metastases Brain metastases are allowed if well controlled and without seizures No distant metastases Active metastases. Known brain metastases, unless stable for at least 28 days Known symptomatic or uncontrolled brain metastases or epidural disease Known untreated, symptomatic, or progressive brain metastases; presence of carcinomatous meningitis; history of intracranial hemorrhage; or brain metastases requiring chronic steroids Patients with treated, stable brain metastases are allowed to enroll; patients must be at least 4 weeks from brain radiation and off any medications used to treat brain metastases including steroids; patients are allowed to be on anti-epileptic medications that are not contraindicated Active brain metastases or unevaluated neurologic symptoms suggestive of brain metastases; subjects with brain metastasis and documented stable disease for > 6 weeks may be included in this study; brain metastases will not be considered measurable lesions for the purposes of this trial Patients with untreated brain metastases are excluded; however, patients with treated brain metastases are eligible if they are > 4 weeks from therapy completion (including radiation and/or surgery), are clinically stable at the time of study entry and are not receiving corticosteroid therapy at the time of study entry Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases Participants with known brain metastases should be excluded from this clinical trial Participants with known brain metastases Patients with known brain metastases will only be eligible after their tumors have been treated with definitive resection and/or radiotherapy and they are neurologically stable for at least 1 month off steroids. Patients with known active, untreated brain metastases should be excluded from this clinical trial. Those with previously treated inactive brain metastases with no evidence of active disease documented on brain MRI at least 4 weeks after radiation and off all steroids may be eligible. Any known metastases Clinical evidence of brain metastases or carcinomatous meningitis Any known untreated brain metastases. Treated subjects must be stable for 4 weeks after completion of that treatment, with image documentation required. Patients must have no clinical symptoms from brain metastases and must be either off steroids or on a stable dose of steroids for at least 2 weeks prior to protocol enrollment. Patients with known leptomeningeal metastases are excluded, even if treated. Known uncontrolled brain metastases. Stable brain metastases either treated or being treated with a stable dose of steroids/anticonvulsants Any known symptomatic brain metastases requiring steroids. Patients with treated brain metastases must be stable for 4 weeks after completion of that treatment, with image documentation required. Patients must have no clinical symptoms from brain metastases and must be either off steroids or on a stable dose of steroids for at least 2 weeks prior to protocol enrollment. Patients with known leptomeningeal metastases are excluded, even if treated. History or evidence of brain metastases Patients with known brain metastases are NOT eligible for participation Brain metastases are excluded unless: \r\n* All known lesions were previously treated with surgery or stereotactic surgery (whole-brain radiation is not allowed unless given after definitive treatment with surgery or stereotactic surgery), AND \r\n* Brain lesion(s), if still present, must be confirmed stable (i.e., no increase in lesion size) for >= 12 weeks prior to D1 of study treatment (stability must be confirmed with two consecutive magnetic resonance image [MRI] or computed tomography [CT] scans with contrast, AND \r\n* Asymptomatic with no corticosteroid requirements for >= 4 weeks prior to D1 of study treatment, AND \r\n* Treatment with any cytochrome P450 (CYP) enzyme inducing anticonvulsants occurred < 4 weeks prior to D1 of study treatment \r\nNOTE: if study subject has history of brain metastasis, but currently has no evidence of disease in brain (NED), confirmation by two consecutive scans separated by >= 6 weeks prior to D1 of treatment is required Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events Patients with known brain metastases Patients with brain metastases may participate if they have undergone appropriate treatment for the lesion(s), are at least two weeks post treatment without evidence for post-treatment progression, have no significant neurologic symptoms, and no longer require steroids for the reason of brain metastases; patients with symptoms suggestive of central nervous system (CNS) metastases should be evaluated with imaging prior to study participation The subject has active brain metastases or epidural disease; subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain scans are not required to confirm eligibility Patient must not have known brain metastases; patients with known brain metastases must be excluded from this clinical trial Documented and ongoing brain metastases Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases Participants with known brain metastases should be excluded from this clinical trial; does not apply to group C Documented brain metastases Symptomatic or clinically active brain metastases Absence of brain metastases as confirmed by imaging of the brain by MRI or CT brain with contrast performed at baseline screening Patients with symptomatic brain metastases will be excluded from trial secondary to poor prognosis; however, patients who have had treatment for their brain metastasis and whose brain disease has remained stable for 3 months without steroid therapy may be enrolled Patients with stable brain metastases are eligible for this trial; stable brain metastases defined as stable disease for one month and not on active treatment including steroids Concurrent radiation therapy is not allowed with the exception of brain metastases developing on study treatment The participant has active brain metastases or epidural disease (Note: participants with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain scans are not required to confirm eligibility) Patients with active or untreated brain metastases; treated brain metastases must have been stable for at least 2 months Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to enrollment in the study. Patients with a history of brain metastases must have a head CT with contrast to document stable disease prior to randomization in the study. Patients with known brain metastases should be excluded from this clinical trial Patients with active brain metastases. Patients with prior history of brain metastasis who have undergone local therapy (i.e. metastatectomy and/or radiation) and show no evidence of local recurrence or progression over the past 6 months are eligible Known presence of metastases Untreated or progressive brain metastases; patients with treated brain metastases not requiring chronic corticosteroids for symptom control are eligible Subjects with uncontrolled brain metastases; subjects with brain metastases must have stable neurologic status following local therapy (surgery or radiation) for at least 4 weeks, be off of steroids, and must be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events Known central nervous system (CNS) disease, except for treated brain metastasis; Note: treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS); gamma knife, linear accelerator (LINAC), or equivalent or a combination as deemed appropriate by the treating physician; patients with CNS metastases treated by neurosurgical resection or brain biopsy performed =< 3 months prior to randomization will be excluded; Note: craniotomy or intracranial biopsy site must be adequately healed, free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of randomization; study treatment should be initiated > 28 days following the last surgical procedure (including biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) Subjects with no brain metastases or a history of previously treated brain metastases who:\r\n* Have been treated by surgery or stereotactic radiosurgery (SRS) at least 4 weeks prior to enrollment\r\n* AND have a baseline magnetic resonance imaging (MRI) that shows no evidence of active intracranial disease\r\n* AND have not had treatment with steroids within 1 week of study enrollment\r\n* Neuroblastoma (NB): Concurrent use of steroids as a supportive medication, e.g. for appetite stimulation is allowed, but must comply with the doses listed CNS or Brain metastases Patients with evidence upon physical examination of brain tumor and any brain metastases A history of or evidence of brain metastases or leptomeningeal disease. Subjects with known untreated brain metastases; subjects with known, treated brain metastases must be stable with no symptoms for four weeks after completion of that treatment, with image documentation required, and must either be off steroids or on a stable dose of steroids for at least two weeks prior to protocol enrollment; subjects with known leptomeningeal metastases are excluded, even if adequately treated; subjects without known brain metastases do not require radiologic imaging prior to enrollment Known central nervous system (CNS) disease, except for treated brain metastases; treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT]) during the screening period; anticonvulsants (stable dose) are allowed; treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, linear accelerator [LINAC], or equivalent) or a combination as deemed appropriate by the treating physician; patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day -3 will be excluded Subjects with known central nervous system (CNS) metastases must have received whole-brain radiation or other appropriate therapy not less than 4 weeks prior to starting the study drug, and exhibit clinical stability of brain disease as judged by the treating physician Patients with a history or evidence of central nervous system (CNS) disease, including brain tumor, seizures not controlled with standard medical therapy or any brain metastases Known central nervous system (CNS) disease, except for treated brain metastasis; treated brain\r\nmetastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT]) during the screening period; anticonvulsants (stable doses) are allowed; treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, linear accelerator [LINAC], or equivalent) or a combination as deemed appropriate by the treating physician; patients with CNS metastases treated by neurosurgical resection or brain biopsy performed < 4 weeks prior to Day 1 will be excluded Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible; patients with surgically resected brain metastases are eligible Active brain metastases Known brain metastases Previously treated NSCLC with asymptomatic brain metastases (eligible for Arm M) See additional details below No more than 4 brain metastases Each brain metastases ?3 cm in size Subjects with known brain metastases and/or unresectable sarcoma Active brain metastases with the exception of subject has been treated and are asymptomatic and there has been no evidence of CNS progression for at least 4 weeks of first dose of MEDI-573 Patients with leptomeningeal metastases Uncontrolled brain metastases and infections; patients with brain metastases treated with gamma knife (GK) or whole brain radiation within 24 hours of registration Four or fewer brain metastases (as defined on the pre-operative MRI or CT brain scan) and status post resection of one of the lesions Any unresected lesions must measure < 3.0 cm in maximal extent on the contrasted MRI or CT brain scan obtained =< 35 days prior to pre-registration; the unresected lesions will be treated with SRS; Note: the metastases size restriction does not apply to the resected brain metastasis; with resected brain metastases only surgical cavity size determines eligibility Symptomatic brain metastases (prior treatment and stable metastases are allowed) Patients with active brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Participants with metastases Subjects with brain metastases are excluded if their brain metastases are: Previously untreated brain metastases; Note: patients with previously treated brain metastases are allowed as long as these are radiologically stable for >= 3 months and the patient is off steroids for >= 4 weeks Active seizure disorder or evidence of brain metastases; (appropriate imaging should be done to rule out brain metastases) Known brain metastases Unstable or symptomatic brain metastases (however, patients with stable or treated brain metastases who do not require steroids at doses above those permitted for control of symptoms may be enrolled) Patients with known brain metastases are excluded from this clinical trial, with the exception of patients whose brain metastatic disease status has remained stable for >= 3 months after treatment of the brain metastases, without steroids or anti-seizure medications; these patients may be enrolled at the discretion of the principal investigator Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases Known or suspected brain metastases Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to study treatment Patients with hemorrhagic brain metastases Patients with solitary brain metastases previously treated with surgery or stereotactic radiosurgery (+/- whole brain radiation therapy [WBRT]) and currently controlled at the time of study enrollment are also eligible but must have an magnetic resonance imaging (MRI) within 80 days prior to study registration; patients with a history of multiple brain metastases must have an MRI showing no active brain metastases within 80 days prior to study registration History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medication for 6 weeks prior to the first dose of study drug; screening with CNS imaging studies (CT or magnetic resonance imaging [MRI]) is required only if clinically indicated or if the subject has a history of CNS metastases; treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period; anticonvulsants will not be allowed; treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; gamma knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician; patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 will be excluded EXPANSION COHORT ONLY: History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medication for 6 weeks prior to the first dose of study drug; screening with CNS imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is required only if clinically indicated or if the subject has a history of CNS metastases; treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period; anticonvulsants will not be allowed; treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; gamma knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician; patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 will be excluded Patients with brain metastases Patients with distant metastases Subjects with known brain metastases will be eligible if they have completed the primary brain therapy (such as whole brain radiotherapy, stereotactic radiosurgery, or complete surgical resection) and if they have remained clinically stable, asymptomatic, and off of steroids for at least 28 days Known brain metastases or cranial epidural disease unless adequately treated and stable for at least 4 weeks before first dose of study treatment. Participants with active brain metastases; stable treated brain metastases are allowed (this includes participants who have documented radiologic stability at least 4 weeks after radiotherapy, and do not require systemic steroids for management of symptoms from central nervous system [CNS] metastatic lesions) History of leptomeningeal carcinomatosis or active brain metastases receiving concurrent treatment inclusive of but not limited to surgery, radiation and/or corticosteroids; Note: brain metastases that have been treated for anticancer purposes where there has been no magnetic resonance imaging (MRI) evidence of progression for at least 8 weeks after treatment are permitted on study Has known central nervous system (ie, brain and/or spinal cord) metastases and/or carcinomatous meningitis. Participants with brain metastases may participate only if they satisfy all of the following: Has no evidence of new or enlarging brain metastases confirmed by post-treatment repeat brain imaging performed ?3 weeks after pre-treatment brain imaging, and Subjects with previously treated progressing brain metastases are excluded from the study Subjects with known brain metastases and contraindications to undergo contrast MRI imaging of the brain are excluded from the study Known active CNS metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided that they are stable with no evidence of progression by imaging, and all neurologic symptoms have returned to baseline, and should not be using corticosteroids for at least 7 days prior to study treatment. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids Previously documented or current brain metastases. Subjects with symptomatic uncontrolled brain metastases; Has known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability. Active central nervous system metastases. Patients with a history of brain metastases may be eligible, provided they have been definitively treated and are clinically stable, after discussion with sponsor. Treated or untreated leptomeningeal disease is not permitted. Untreated brain metastases Primary brain tumors or CNS metastases; Participants with central nervous system (CNS) metastases are not eligible, unless they have completed local therapy (eg, whole brain radiation therapy (WBRT), surgery or radiosurgery) and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs (eg, radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment Patients with untreated brain metastases, spinal cord compression, or evidence of symptomatic brain metastases or leptomeningeal disease as noted on computed tomography (CT) or MRI scans should not be included on this study; screening imaging to rule out brain metastases is not required for screening, but should be performed prior to study enrollment if clinically indicated; patients with treated brain metastases and resolution of any associated symptoms must demonstrate stable post-therapeutic imaging for at least 6 months following therapy prior to starting study drug Evidence of distant metastases Patients with known, untreated brain metastases; patients with treated (irradiated or resected) brain metastases are eligible if treatment was completed more than 28 days prior to study entry and if clinical neurologic function is stable Patients with known active or symptomatic brain metastases prior to vaccination. Patients with known brain metastases should be excluded as this would qualify as stage IV/metastatic disease Known brain metastases Additional unresected brain metastases (up to 2) must have a maximum diameter of less than or equal to 3 cm Patients with a history or clinical evidence of brain metastasis must have completed radiation therapy or surgical treatment of brain lesions and have no evidence of central nervous system (CNS) progression for at least eight weeks at the time of registration; patients must not require corticosteroids for treatment of cerebral edema from brain metastases; patients must be evaluated with a head magnetic resonance imaging (MRI) within 4 weeks prior to registration No prior radiotherapy to the brain Brain metastases Patients with known symptomatic brain metastases requiring steroids. Patients with stable, treated brain metastases are eligible for this trial. However, patients must not have required steroid treatment for their brain metastases within 30 days of Screening. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids at a dose exceeding 10mg of prednisone per day or its equivalent for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability Patients with untreated symptomatic brain metastases will be excluded from this study; those with treated brain metastases or untreated but asymptomatic sub-centimeter brain metastases will be allowed as long as they are neurologically asymptomatic and off steroids Subjects with no brain metastases or a history of previously treated brain metastases who:\r\n* Have been treated by surgery or stereotactic radiosurgery (SRS) at least 4 weeks prior to enrollment\r\n* AND have a baseline magnetic resonance imaging (MRI) that shows no evidence of active intracranial disease\r\n* AND have not had treatment with steroids for brain metastases within 1 week of study enrollment Brain metastases Leptomeningeal disease or any untreated or symptomatic brain metastases, unless the following criteria are met: brain metastases are stable and have been previously treated with either whole-brain radiotherapy or gamma-knife surgery Subjects with previously untreated or uncontrolled brain metastases. Active brain metastases. Active brain metastases or leptomeningeal metastases (carcinomatous meningitis); subjects with brain metastases are eligible if these have been treated and there is no evidence of progression for at least 2 weeks after treatment is complete and corticosteroid dose is stable (and equivalent dose of < 10 mg prednisone) for at least 2 weeks Patients with untreated symptomatic brain metastases; patients with treated brain metastases will be allowed if brain imaging obtained within 30 days of trial enrollment reveals stable disease; patients with small asymptomatic brain metastasis are allowed to enroll; patients on steroids doses higher than 10 mg of prednisone (or its equivalent) are excluded Has brain metastases with evolving neurologic symptoms or a steroid requirement. Symptomatic brain metastases (patients with asymptomatic brain metastases may be eligible provided other criteria are met) Symptomatic brain metastases. Known symptomatic brain mets or leptomeningeal involvement Evidence of distant metastases Patients with known brain metastases unless treated with an appropriate modality with no evidence of progression/recurrence for > 3 months Patients with brain metastases are eligible if asymptomatic and neurologically stable for at least 4 weeks and are not taking any medications contraindicated Patients with treated brain metastases (received definitive radiation and/or underwent surgical resection) are eligible for therapy on this protocol; patients with clinical evidence of active brain metastases are ineligible for therapy on this protocol History of brain metastases unless irradiated ? 2 weeks prior to first study treatment and stable without requirement of corticosteroids. Subjects who have new or progressive brain or meningeal or spinal metastases Active brain metastases or leptomeningeal metastases; subjects with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 42 weeks after treatment is complete and within 28 days prior to first dose of study drug administration; there must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalent) for at least 2 weeks prior to study drug administration Active metastases. Documented evidence of distant metastases or brain metastases Known brain metastases. Subject has known brain metastases. Patients with known brain metastases should be excluded from this clinical trial Symptomatic brain metastases Symptomatic brain metastases Symptomatic brain metastases. Symptomatic brain metastases. Brain metastases (except if all known lesions were previously treated with surgery or stereotactic radiosurgery and lesions, if still present, are confirmed stable for >= 2 weeks prior to enrollment, and are asymptomatic with no corticosteroid requirements for >= 2 weeks prior to randomization, and no enzyme inducing anticonvulsants for >= 2 weeks prior to randomization); brain MRI or CT is required at screening Symptomatic metastatic brain or meningeal tumors; baseline brain imaging is not required Patients with known brain metastases should be excluded from this clinical trial Patients with known active brain metastases or carcinomatous meningitis are excluded from this clinical trial; patients whose brain metastatic disease status has remained stable for >= 4 weeks following treatment of brain metastases are eligible to participate at the discretion of the principal investigator Subjects with asymptomatic brain metastases found on screening MRI may be entered into Phase 1b or into Group 2 of the Phase 2a without prior radiation therapy to the brain. Subjects with minimally symptomatic brain metastases found on screening MRI may be entered into Phase 1b or into Group 2 of the Phase 2a without prior radiation therapy to the brain if they do not require immediate surgical or radiation therapy Subjects with leptomeningeal metastases may or may not have brain metastases. When brain metastases are present, they do not need to have progressed after radiation therapy The participant has active brain metastases or epidural disease; participants with stable brain metastases previously treated with whole brain radiation or radiosurgery or participants with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 4 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain imaging with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans for participants with known brain metastases is required to confirm eligibility Clinically active brain metastases Brain metastases requiring steroids Known brain metastases, or untreated meningeal/dural disease Brain biopsy or resection; Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible Patients with known brain metastases are excluded from this study Known brain metastases (unless asymptomatic and treated) or leptomeningeal metastases, including suspected leptomeningeal spread with positive cytology Patients with known brain metastases should be excluded from this clinical trial Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible; patients with surgically resectable brain metastases are eligible Patients with known brain metastases should have their brain metastases treated prior to enrollment on this protocol; subjects may enroll on this trial after completion of whole brain radiation therapy and/or stereotactic radiosurgery, provided they are clinically without evidence of progressive brain metastases Known brain, leptomeningeal or epidural metastases (unless treated and well controlled for at least 3 months) Subjects with known or suspected brain metastases, primary brain tumors, or brain as the only site of disease Patients with uncontrolled brain metastases; patients with brain metastases must have stable neurologic status following local therapy (surgery or radiation) for at least 4 weeks, and must be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; patients may be treated with steroids as clinically indicated Brain metastases requiring steroids. 10. Uncontrolled or severe concurrent medical condition (including uncontrolled brain metastases). Stable brain metastases either previously treated or being treated with a stable dose of steroids and/or anticonvulsants (no dose change within 28 days prior to the first dose of study drug) will be allowed. Progressing brain metastases (unless previously treated and stable disease for a period of greater than or equal to 3 months on repeat MRI following definitive treatment). Untreated brain metastases. (Brain metastases that have been treated, which no longer require corticosteroid therapy and are without progression by MRI at least 6 weeks after definitive therapy are acceptable.) Patients with known brain metastases should be excluded from this clinical trial At the time of day 1 of the study, patients with brain metastases must be asymptomatic and: 1) at least 8 weeks without tumor progression after any whole brain radiotherapy, 2) at least 4 weeks since craniotomy and resection or stereotactic radiosurgery, 3) at least 3 weeks without new brain metastases as evidenced by MRI Participants with treated brain metastases are eligible for study participation; participants may not receive ongoing treatment with steroids at screening, anticonvulsants (at stable dose) are allowed The subject has active brain metastases or epidural disease (note: subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain scans are not required to confirm eligibility) Patients with uncontrolled brain metastasis; Note: patients with brain metastases must have stable neurologic status following local therapy (surgery or radiation) for at least 2 weeks, and must be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events Patients must have no clinical evidence of active brain metastasis. Patients with a history of brain metastases must meet all of the following criteria: History or clinical evidence of brain metastases Patients with brain metastases unless all of their metastatic brain lesions have been resected or treated with stereotactic radiotherapy with gamma rays and they are off corticosteroids; patient should not have significant brain edema; patients with spinal cord compression and leptomeningeal disease; patients with treated central nervous system (CNS) metastases are not eligible for the neoadjuvant treatment cohort in Phase II; no major surgery or radiation therapy within 21 days before starting treatment Patients with symptomatic brain metastases should be excluded from this clinical trial; however, patients who have had treatment for their brain metastases and whose brain metastatic disease status has remained stable for at least 4-6 weeks without steroids may be enrolled at the discretion of the principal investigator Patients who are taking bevacizumab or have taken bevacizumab within the past 2 weeks for treatment of their brain metastases Patients with brain metastases are allowed only if they are off systemic corticosteroids and stable for a minimum of 8 weeks Has known untreated or symptomatic brain metastases; Patients with symptomatic brain metastases should be excluded from this clinical trial; however, patients who have had treatment for their brain metastases and whose brain metastatic disease status has remained stable for at least 1 week after the end of brain radiation may be enrolled to undergo molecular profiling at the discretion of the principal investigator; in addition, brain metastatic disease should be stable for at least 4 weeks, before the patients can be enrolled in any of the experimental treatment arms Presence of parenchymal brain metastases; patients with neurological symptoms must have a CT or magnetic resonance imaging (MRI) of the brain showing no metastases within 60 days of enrollment Patients with known brain metastases Participants with known brain metastases should be excluded from this clinical trial Active brain metastases (untreated brain metastases or growth on imaging as defined below) or leptomeningeal disease are not allowed; subjects with brain metastases are eligible if these have been treated and there is no MRI (or CT if MRI contraindicated) evidence of progression for at least 8 weeks after treatment for these metastases is complete and within 28 days prior to first study treatment Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with a prior history of brain metastases are eligible provided:\r\n* The brain metastases have been treated\r\n* The patient is asymptomatic from the brain metastases\r\n* Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration Untreated brain metastasis; patients with treated brain metastases who are off steroids are eligible Patients with known brain metastases or carcinomatous meningitis are excluded from this clinical trial, with the exception of patients with brain metastatic disease that has previously been treated and remained stable on MRI >= 2 months after treatment, without steroids or anti-epileptic medications; these patients may be enrolled at the discretion of the principal investigator The subject has active brain metastases or epidural disease; subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain imaging with contrast-enhanced CT or magnetic resonance imaging (MRI) scans for subjects with known brain metastases is required to confirm eligibility Active brain metastases or leptomeningeal metastases Presence of symptomatic or uncontrolled brain or central nervous system metastases. Patients with stable, treated brain metastases are eligible for this trial. However, patients must not have required steroid treatment for their brain metastases within 30 days of Screening. Patients with known brain metastases Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases Patients with brain metastases which are stable and have been treated with surgery or irradiation will be eligible for this trial Patients with gliomas or brain metastases who require corticosteroids or anticonvulsants must be on a stable dose of corticosteroids and seizure free for 1 month prior to enrollment; patients with known brain metastases should have had brain irradiation (whole brain or gamma knife) more than 4 weeks before starting the protocol; note that patients should have had their steroids tapered to low dose (i.e., < 1.5 mg of dexamethasone/day) Untreated brain metastases Documented primary brain malignancy or brain metastases. Patients with known active brain metastases are excluded; head computed tomography (CT) is NOT routinely required prior to enrollment; patients with treated, asymptomatic brain metastasis will be eligible for enrollment Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms Subject has known brain metastases Recurrent brain metastases from breast cancer Subjects with no brain metastases or a history of previously treated brain metastases who:\r\n* Have been treated by surgery or stereotactic radiosurgery (SRS) at least 4 weeks prior to enrollment\r\n* AND have a baseline magnetic resonance imaging (MRI) that shows no evidence of active intra cranial disease\r\n* AND have not had treatment with steroids within 1 week of study enrollment\r\n* Neuroblastoma (NB): Concurrent use of steroids as a supportive medication, e.g. for appetite stimulation is allowed Brain or leptomeningeal metastases that are symptomatic and/or requiring treatment Patients with known brain metastases should be excluded from this clinical trial Symptomatic brain metastases Brain metastases that are untreated or symptomatic or require any radiation, surgery,\n or steroid therapy to control symptoms from brain metastases within 1 month of\n randomization Patients with stable brain metastases are eligible for this trial. However, patients must not have required steroid treatment for their brain metastases within 30 days of Screening. No known or suspected (associated neurological signs and symptoms) brain metastases (including leptomeningeal involvement) Patients with history of brain metastases can be enrolled at a minimum of 2 weeks following the completion of surgery, gamma knife or whole brain radiotherapy; repeat brain magnetic resonance imaging (MRI) not required for eligibility Patients with active brain metastases should be excluded from this clinical trial except as noted above Symptomatic central nervous system metastases; subjects with brain metastases that have been previously treated and are stable for 4 weeks are allowed Evidence of active brain metastases, including leptomeningeal involvement (prior evidence of brain metastasis are permitted only if treated and stable and off therapy for >= 2 weeks prior to signing informed consent form; magnetic resonance imaging of the brain (or computed tomography scan w/contrast) is preferred for diagnosis Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms; or any radiation, surgery or other therapy to control symptoms from brain metastases within 2 months prior to first dose of MEDI4276. Patients with untreated central nervous system metastases or local treatment of brain metastases Subject has active central nervous system (CNS) metastases not controlled by prior surgery or radiotherapy (subjects must be off steroids). Subjects with signs or symptoms suggestive of brain metastasis are not eligible unless brain metastases are ruled out by brain MRI/CT. Uncontrolled brain metastases or leptomeningeal involvement; patients with brain metastases are permitted if they have received appropriate therapy and demonstrated control of the brain metastases or leptomeningeal disease following therapy; patients with known brain metastases will require magnetic resonance imaging (MRI) brain to demonstrate disease control prior to enrollment (lack of symptom progression for two weeks off therapeutic doses of steroids, excluding chronic steroids used for control of chronic obstructive pulmonary disease [COPD]) In the investigator's judgment, focal neurologic deficit as a result of metastases in the brain, spine, or other central nervous system disorders. Patients with known brain metastases will be excluded from this clinical trial Evidence of active brain metastases, including leptomeningeal involvement (prior evidence of brain metastasis are permitted only if treated and stable and off therapy for at least 21days prior to signing ICF). MRI of the brain (or CT scan w/contrast) is preferred for diagnosis. Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible; patients with surgically resected brain metastases are eligible Brain metastases Known brain metastases; patients with known brain metastases must be excluded from this clinical trial Patients with known brain metastases will be excluded Documented metastases to brain or meninges. Patients with known brain metastases should be excluded from this clinical trial\r\n* Patients with carcinomatous meningitis should also be excluded \r\n* Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Patients with known brain metastases should be excluded from this clinical trial Untreated brain metastases; brain metastases =< 1 cm and not associated with any focal neurologic deficits are allowed Symptomatic brain metastasis. Participants with brain metastases: Active brain or subdural metastases Patients with untreated central nervous system metastases or local treatment of brain metastases within the last 6 months; patients with stable brain metastasis for 6 months post-intervention are eligible; subjects with chordoma will be eligible regardless of site of disease if other eligibility criteria are met Any known symptomatic brain metastases requiring steroids. Patient with brain metastases that are symptomatic and/or require therapy. Patients must have a CT or MRI scan of the brain to evaluate for CNS disease within 42 days prior to registration; patient must not have brain metastases unless: (1) metastases have been treated and have remained controlled for at least 14 days following treatment or was not treated, but is asymptomatic, AND (2) patient has no residual neurological dysfunction off corticosteroids or anti-convulsants for at least 14 days Patients with known symptomatic brain metastases requiring steroids Active or progressing brain metastases Patients with a prior history of seizures within the past year unrelated to brain metastases Patients with known active progressive brain metastases; patients with prior treated brain metastases are allowed, providing that they were not accompanied by seizures within the past year and that a baseline brain MRI scan prior to study entry demonstrates no current evidence of active brain metastases; all patients with prior treated brain metastases must be stable for > 1 months after treatment and off steroid treatment prior to study enrollment Subjects with brain metastases are excluded if their brain metastases are: Symptomatic; Treated (surgery, radiation therapy) but not clinically and radiographically stable one month after local therapy, OR; Asymptomatic and untreated but > 1 cm in the longest dimension. Subjects with small (<= 1 cm in the longest dimension), asymptomatic brain metastases that do not need immediate local therapy can be enrolled. Subjects on a stable dose of corticosteroids for more than one month, or those who have been off corticosteroids for at least 2 weeks can be enrolled. Subjects must also be off of enzyme-inducing anticonvulsants for more than 4 weeks. Brain metastases requiring steroids Has clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with steroids may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 4 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment (2 weeks for stereotactic radiotherapy). Untreated brain metastases Brain metastases that are:\r\n* Progressive or\r\n* Have required any type of therapy (including radiation, surgery or steroids) to control symptoms from brain metastases within 60 days prior to the first study treatment Active, untreated brain metastases Patients who previously had brain metastases (screening not required) unless they have met all of the following criteria: Patients with treated, stable brain metastases eligible providing treatment was ?4 weeks prior to initiation of study drug, and baseline CT or MRI negative for new brain metastases. Must not require therapy with corticosteroids. Brain metastases are allowed if the patient is asymptomatic or previous steroid treatment was discontinued >= 6 weeks Uncontrolled central nervous system (CNS) metastases are not allowed; subjects with previously treated brain metastases will be allowed if the brain metastases have been treated, toxicities have resolved to grade 1 or baseline and steroids are no longer required; leptomeningeal metastases are not allowed Known brain metastases Patients with prior whole brain irradiation Central nervous system metastases\r\n* Note: Subjects with previously treated (radiotherapy or surgery) brain metastasis that have been stable without steroid treatment for at least 3 months following prior treatment may be enrolled Untreated brain metastases For patients with brain metastases, the following criteria must be met: Previously untreated brain metastases that are asymptomatic and not requiring steroids are permitted. Previously treated brain metastases are permitted if most recent CNS radiographic imaging demonstrates no evidence of CNS disease progression For patients with previously untreated brain metastases, Central Nervous System (CNS) imaging is required at the time of disease imaging throughout treatment. Known brain metastases (systematic screening of patients not mandatory) Patients must be free of active brain metastases by contrast-enhanced computed tomography (CT)/magnetic resonance imaging (MRI) scans within 4 weeks prior to starting the study drugs; if known to have prior brain metastases, must not have evidence of active (enlarging and/or symptomatic lesions) brain disease on two successive MRI evaluations at least 3 months apart (one of which is at least 4 weeks prior to starting the study drugs) Patients with untreated or uncontrolled brain metastases or leptomeningeal disease The patient has a primary brain tumor. Patients may have brain metastases from another primary site. Presence of serious illnesses or medical condition(s) e.g. brain metastases, systemic infection, heart failure Subject must not have known untreated brain or meningeal metastases. CT scans are not required to rule out brain or meningeal metastases unless there is a clinical suspicion of central nervous system disease. Subjects with treated brain metastases that are radiographically or clinically stable for at least 4 weeks after therapy and have no evidence of cavitation or hemorrhage in the brain lesion(s) are eligible, provided that they are asymptomatic and do not require corticosteroids (must have discontinued steroids at least one week prior to study drug administration). Patients with known brain metastases Brain metastases that are untreated or symptomatic, or require any radiation, surgery, or steroid therapy to control symptoms from brain metastases within 14 days of first on-study thrombokinetic study; for patients with newly diagnosed brain metastases or unequivocal progression of brain metastases on screening scans, localized treatment (i.e., surgery, radiosurgery, and/or whole brain radiotherapy) is required before study enrollment; subjects with known brain metastases must have clinically controlled neurologic symptoms, defined as surgical excision and/or radiation therapy followed by 14 days of stable neurologic function prior to the first thrombokinetic procedure; patients with small brain metastases not symptomatic and deemed requiring treatment by managing clinicians or study investigators may be permitted to enroll on study Patients with known brain metastases are excluded unless they have had definitive treatment (e.g. whole brain radiotherapy or surgery or stereotactic radiation) for brain metastases with evidence of stable/improved disease on repeat imaging following definitive treatment Patients with known brain metastases will be excluded from this portion of the clinical trial (which will assess PFS and TTP) Patients with brain or leptomeningeal metastases are allowed on study if the lesions are asymptomatic without neurological signs and clinically stable for at least 2 weeks Current or a prior history of brain metastases or leptomeningeal disease. Must not have rapidly progressive, life-threatening metastases. Presence of any brain metastases detected by MRI or CT with i.v. contrast of the brain at screening. Participants with known brain or spinal cord metastases are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. NOTE: Brain imaging is not required unless the patient has symptoms or physical signs of central nervous system (CNS) disease. Active or progressing brain metastases The subject has uncontrolled metastases to the central nervous system (CNS). Subjects with brain metastases are eligible provided they have shown clinical and radiographic stable disease for at least 28 days after definitive therapy and have not received prior whole brain radiation (Phase 1 only). Known central nervous system (CNS) disease, except for treated brain metastasis; treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT]) during the screening period; anticonvulsants (stable dose) are allowed; treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS) (Gamma Knife, linear accelerator [LINAC], or equivalent) or a combination as deemed appropriate by the treating physician; patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 will be excluded Patients with known uncontrolled brain metastases are excluded; however, patients with stable brain disease (off corticosteroids) at least 2 weeks after completion of appropriate therapy for their brain metastases are eligible Patients with primary brain cancer or known brain metastases should be excluded from this clinical trial Active brain metastases Patient must not have known active brain metastases; patients with previously treated brain metastases are eligible; patients with known brain active metastases must be excluded from this clinical trial Patients with known brain metastases Patients with known brain metastases may be excluded from this study. However, patients may be eligible if scans show limited disease or repeat scans show stable disease in the opinion of the investigator and patients have no ill effect from the metastases. Patients with known untreated brain metastases Uncontrolled brain metastases Known or suspected metastases in the brain Uncontrolled or symptomatic brain metastases that are not stable, require steroids, are potentially life-threatening or that have required radiation within 28 days prior to first dose of study treatment. Patients with known brain metastases are excluded from this clinical trial Any known symptomatic or untreated brain metastases requiring increase of steroid dose within 2 weeks prior to starting on study. Patients with treated brain metastases must be stable for 4 weeks after completion of that treatment. Patients must have no clinical symptoms from brain metastases and must be either off steroids or on a stable dose of steroids for at least 2 weeks prior to protocol enrollment. Patients with known leptomeningeal metastases are excluded, even if treated. Patients with active brain metastases or carcinomatous meningitis or epidural disease are excluded from this clinical trial; subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation who are asymptomatic and have remained stable for 4 weeks and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain imaging with contrast-enhanced CT or MRI scans for subjects with known brain metastases is required to confirm eligibility Leptomeningeal metastases, hemorrhagic metastases, presence of midline shift; please note: leptomeningeal metastases may be allowed if it is limited to cranial metastasis (magnetic resonance imaging [MRI] spine should be completed, within 4 weeks of enrollment, to show that no other leptomeningeal metastases is present) and is not the only metastasis present in the brain Known uncontrolled symptomatic brain metastases or cranial epidural disease; subjects previously treated and on stable dose of corticosteroids and/or anticonvulsants for > 10 days, or not requiring such medications, are eligible; baseline brain scans are not required to confirm eligibility Symptomatic uncontrolled brain or leptomeningeal metastases Symptomatic uncontrolled brain or leptomeningeal metastases. Active or untreated brain metastases Participants with primary brain tumors or disease metastatic to the brain. Patients with treated, stable brain metastases are allowed to enroll; patients must be at least 4 weeks from radiation and off any medications used to treat brain metastases including steroids; patients are allowed to be on antiepileptic medications that are not metabolized by cytochrome P450 3A4 or 2C19; patients with brain metastases must have stable brain imaging within 4 weeks prior to starting study Participants with known brain metastases that are symptomatic and require corticosteroids are excluded Patients with known brain metastases should be excluded from this clinical trial Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible Patients with 3 or less brain metastases that are less than 1 cm in diameter and asymptomatic are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible; patients with surgically resected brain metastases are eligible Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases Presence of brain metastases Patients with known brain metastases should be excluded from this clinical trial Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms Brain metastases with symptoms or requiring treatment Patients with untreated brain metastases should be excluded from this clinical trial Known brain metastases not radiographically stable for ?3 months or leptomeningeal disease Known history or evidence of brain metastases Subjects with brain metastases Symptomatic and progressive or corticosteroid-requiring documented brain metastases Up to 2 additional intact brain metastases to be treated with stereotactic radiosurgery (SRS) alone First presentation of brain metastases Previous brain radiotherapy (SRS or whole brain radiation therapy [WBRT]) Patients with known brain metastases will be excluded from this clinical trial Patients with brain metastases should be excluded from this clinical trial except as noted above Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases; treated brain metastases must have been stable for at least 2 months Patients with known brain metastases should be excluded from this clinical trial Untreated brain metastases (or local treatment of brain metastases within the last three months) Untreated brain metastases Patients with history or evidence upon physical examination of central nervous system (CNS) disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months of the first date of treatment on this study; patients with treated brain metastases can enter the study; treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT]) during the screening period; anticonvulsants (stable dose) are allowed; treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, linear accelerator [LINAC], or equivalent) or a combination as deemed appropriate by the treating physician; patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 will be excluded For lung metastases, no more than 2 metastases treated in one setting Central nervous system (CNS) metastases: Patients who remain asymptomatic after successful definitive treatment of brain metastases (i.e., surgical resection, curative whole brain irradiation, stereotactic radiation therapy, or a combination of these) demonstrating stable or improved radiographic appearance on magnetic resonance imaging (MRI) scan >= 3 months after completion of treatment and no signs of cerebral edema are eligible Subjects may have distant metastasis, including brain metastases. Subjects with known brain metastases are eligible if: They have received standard anti-tumor treatment for their brain metastases without encephalopathy; Uncontrolled brain or all leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases The participant has uncontrolled brain or leptomeningeal metastases Known brain metastases (scan required at screening) Brain stem involvement allowed Known active central nervous system (CNS) metastases; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids > 10 mg/day of prednisone or equivalent; the exception does not include carcinomatosus meningitis which is excluded regardless of clinical stability Patients with known brain metastases are excluded from this clinical trial Known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to day 1 and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment Patients are excluded if they have active brain metastases or leptomeningeal metastases; subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for (lowest minimum is 4 weeks or more) after treatment is complete and within 28 days prior to the first dose of nivolumab administration; there must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration Brain metastases or spinal cord compression unless asymptomatic or treated and stable off steroids and anti-convulsants for at least 14 days prior to study treatment start; patients with suspected brain metastases at screening should have a CT/magnetic resonance imaging (MRI) of the brain prior to study entry Prior whole brain irradiation Patients with asymptomatic brain metastases are allowed, as long as they are treated, stable, and do not require treatment with anticonvulsants or escalating doses of steroids; maximum daily dose of steroids should be prednisone 10 mg or equivalent; radiation therapy for brain metastases must be completed at least 14 days prior to treatment on protocol; patients with untreated brain metastases who are stable, asymptomatic and not requiring treatment with anticonvulsants or escalating doses of steroids are eligible Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with no brain metastases or a history of previously treated brain metastases who have been treated by surgery or stereotactic radiosurgery at least 4 weeks prior to enrollment and have a baseline MRI that shows no evidence of active intracranial disease and have not had treatment with steroids within 1 week of study enrollment Patients with brain metastases are excluded Patients who have a history of brain metastasis are eligible for the study provided that all the following criteria are met:\r\n* Brain metastases which have been treated,\r\n* No evidence of disease progression for >= 3 months or hemorrhage after treatment,\r\n* Off-treatment with dexamethasone for 4 weeks before administration of the first dosing,\r\n* No ongoing requirement for dexamethasone or anti-epileptic drugs Symptomatic, untreated or unstable central nervous system or leptomeningeal metastases; (patients with treated and stable brain metastases [confirmed by 2 scans at least 4 weeks apart], with no evidence of cavitation or hemorrhage in the brain lesion are eligible provided that they are asymptomatic and do not require corticosteroids) Patients with known brain metastases should be excluded from this clinical trial Patients with known symptomatic brain metastases requiring steroids and/or antiepileptic therapy; patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study treatment, and have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable; patients with leptomeningeal involvement are excluded Uncontrolled brain metastases; patients with brain metastases are permitted if they have received appropriate therapy and demonstrated control of the brain metastases following therapy; patients with known brain metastases will require magnetic resonance imaging (MRI) brain to demonstrate disease control prior to enrollment (lack of symptom progression for two weeks off therapeutic doses of steroids, excluding chronic steroids used for control of chronic obstructive pulmonary disease [COPD]) Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible; patients with surgically resected brain metastases are eligible Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible; lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible Known brain metastases Patients with known brain metastases should be excluded from this clinical trial Stable, treated brain metastases are allowed; stable brain metastases are defined as stable on magnetic resonance imaging (MRI) 4 weeks after the completion of radiation, and currently asymptomatic no longer requiring corticosteroids for 2 weeks prior to the initiation of study drug Prior surgical resection for brain metastases Leptomeningeal metastases Patient has evidence of clinically unstable brain metastases (controlled and stable brain metastasis must be previously treated and asymptomatic) No conditions that may compromise blood-brain barrier permeability (e.g., multiple sclerosis, recent brain trauma, Alzheimer’s disease, or uncontrolled seizures)\r\n* No symptomatic and untreated brain metastases; patients will be eligible for study if radiation therapy for brain metastases was completed at least 7 days prior to registration\r\n* Patients having received stereotactic radiation will be eligible if the radiation was completed at least 7 days prior to registration\r\n* Patients having undergone surgical resection of brain metastases will be eligible after they have healed and recovered from the surgical intervention sufficiently to start systemic treatment for NSCLC, as determined by a neurosurgeon\r\n* No known leptomeningeal carcinomatosis Patients who present with symptomatic brain radionecrosis after they have received radiosurgery for brain metastases from primary solid tumor including but not limited to lung, breast, colorectal cancer but excluding melanoma, choriocarcinoma, renal cell carcinoma or gliomas Have distant metastases Presence of symptomatic brain metastases at time of study consent process; patients with history of treated brain metastases are eligible if they are not symptomatic at the time of study enrollment Untreated or symptomatic brain metastases or leptomeningeal disease Patient has a condition that may have affected the permeability of the blood-brain barrier (e.g., known brain metastases, meningeal metastases, brain injury, multiple sclerosis, recent brain injury, uncontrolled epilepsy) 1 to 10 brain metastases (mets) (no more than two lesions and/or cavities >= 3 cm in maximum diameter) Leptomeningeal metastases Patients with known brain metastases; Patients with known brain metastases should be excluded from this clinical trial; patients with carcinomatous meningitis should also be excluded; patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging using the identical imaging modality for each assessment, either magnetic resonance imaging [MRI] or computed tomography [CT] scan, for at least 4 weeks before the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days before trial treatment Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms; participants with previously diagnosed brain metastases are eligible if they have completed treatment at least 4 weeks prior to registration, are neurologically stable and absence of new neurologic symptoms for the last 4 weeks prior to study entry, and have recovered from the effects of radiotherapy or surgery; any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 2 weeks before the first study drug; treatment for brain metastases may have included whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating physician Subjects with active brain metastases or leptomeningeal metastases Subject has known active brain or leptomeningeal metastases. Subjects with prior history of brain metastasis who have undergone local therapy (i.e. metastatectomy and/or radiation) and show no evidence of local recurrence or progression over the past 3 months prior to screening are eligible. Participants with known brain metastases should be excluded from this clinical trial Brain metastases that are symptomatic or untreated or that require current therapy. Patients with known distant metastases or other malignancies Presence of brain metastases Patients with brain tumors Patients with untreated brain metastases, as determined by treating oncologist, will be excluded from this clinical trial; patients with treated brain metastasis are eligible for this trial, providing they have completed treatment at least one day prior to registration Patients with either a malignant central nervous system (CNS)-primary cancer or with brain metastases; patients do not need to undergo brain imaging unless indicated per standard workup and management (e.g. advanced stage lung cancer receiving definitive therapy) Metastases to the brain Primary brain tumors Metastases to the brain Primary brain cancer (presumed gliomas with no radiographic or clinical evidence of metastatic disease to the brain) SUBJECT: Must be at least 1 year post completion of radiation therapy to the brain or brain and spine. Distant metastases Participant had breast cancer with brain metastases Participants with known brain metastases Patients with known brain metastases will be excluded from this clinical trial Radiographic evidence of brain metastases and/or ipsilateral lung metastases/malignant pleural effusion Metastases to the brain Brain metastases outside a 5-mm margin around either hippocampus must be visible on contrast-enhanced magnetic resonance imaging (MRI) performed =< 21 days prior to Step 1 registration; an allowed exception, regarding ability to image brain metastases, would be that patients who had undergone radiosurgery or surgical resection and are planning adjuvant WBRT do not have to have visible disease but do need a pre-surgery MRI or computed tomography (CT) scan demonstrating brain metastases; however, the brain metastases could not have been within 5 mm of either hippocampus Patients with definitive leptomeningeal metastases History of epilepsy, brain damage, use of anticonvulsants for seizure prevention, concurrently using ketamine, symptomatic brain metastases Patients with known brain metastases, history of brain metastases or radiation to the brain. Patients with history of epilepsy, brain damage, or symptomatic brain metastases. Subjects who have new or progressive brain or meningeal or spinal metastases. Untreated brain metastases. Subjects must have completed treatment for brain metastasis, and be neurologically stable off steroids, for at least 28 days prior to first dose of study drug Active brain metastases or leptomeningeal metastases; subjects with treated brain metastases are eligible if they meet all of the following criteria:\r\n* Must be at least 28 days since craniotomy and resection, stereotactic radiosurgery, or whole brain radiotherapy\r\n* Must have no evidence of progression for at least 4 weeks after treatment is complete and within 28 days prior to first dose of study drug administration\r\n* Must have no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis;\r\nsubjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to study treatment Have had known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for CNS involvement for at least one week prior to trial treatment; patients with primary brain tumors are not eligible; however, as patients are completing abiraterone therapy, they will be allowed to continue up to 10 mg/day of prednisone Patients with a prior history of brain metastases are eligible provided:\r\n* The brain metastases have been treated \r\n* The patient is asymptomatic from the brain metastases\r\n* Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration \r\n* The brain metastases are stable on pre-registration imaging Patients with active or untreated brain metastases or leptomeningeal metastases are excluded from this clinical trial; NOTE: patients with previously treated brain metastases must have stable neurologic status and magnetic resonance imaging (MRI) imaging following local therapy (surgery or radiation) for at least 4 weeks, with no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration (stable low dose dexamethasone allowed at discretion of protocol chair) Participant has untreated brain or meningeal metastases. Any past neurologic insult that is known to affect brain function such as traumatic brain injury, dementia, encephalopathy, etc. Symptomatic and/or untreated brain metastases Patient must not have brain metastases present prior to initiation of initial therapy or PCI Has distant metastases Patients with known distant metastases or other malignancies Have clinical evidence of lymphedema, current bowel obstruction, or symptomatic brain metastases, as determined by their treating oncologist. Patients with known brain metastases should be excluded from this clinical trial Participants with known brain metastases should be excluded from this clinical trial Known brain metastases Patients with brain metastases are allowed on this study (concurrent treatment with steroids is allowed) Metastatic cancer to the brain for which palliative whole brain radiotherapy is recommended. Previous brain radiotherapy Diagnosis of primary brain tumors Known history of brain metastases Subjects with known or history of brain metastases or leptomeningeal disease: subjects with neurological symptoms must undergo a contrast CT scan or MRI of the brain within 28 days prior to randomization to exclude active brain metastasis. Imaging of the central nervous system (CNS) is otherwise not required. Patients with known symptomatic brain metastases should be excluded from this clinical trial Patients with active CNS or other brain metastases Participants with symptomatic uncontrolled brain metastases; a scan to confirm the absence of brain metastases is not required Patients with brain metastases who require corticosteroids or non-enzyme inducing anticonvulsants must be on a stable dose of corticosteroids and seizure free for 1 month prior to enrollment; patients with known brain metastases should have completed brain irradiation (whole brain or gamma knife) more than 4 weeks before starting the protocol; patients on enzyme inducing anticonvulsants are not eligible; note that patients should have had their steroids tapered to low dose (i.e. < 1.5 mg of dexamethasone/day) due to the potential for higher dexamethasone doses to induce CYP3A4 Patients with known active brain metastases are excluded; patients with a history of central nervous system (CNS) metastases that have been treated must be stable with no symptoms for > 3 months after completion of that treatment and off steroid treatment, with image documentation required prior to study enrollment Any known symptomatic brain metastases requiring steroids. Patients with treated brain metastases must be stable for 4 weeks after completion of that treatment, with image documentation required. Patients must have no clinical symptoms from brain metastases and must be either off steroids or on a stable dose of steroids for at least 2 weeks prior to protocol enrollment. Patients with known leptomeningeal metastases are excluded, even if treated No history of seizures related to the brain metastases or LMD. Participants with known brain metastases, or any other metastases from cancer Brain metastases requiring focal or whole brain radiation will be excluded Radiologic evidence of new and/or progressive brain metastases (>= 10 mm in longest dimension) by MRI imaging of the brain Planned WBRT based on number (>= 3 lesions) and/or size (>= 1 cm) of brain metastases Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are clinically stable and are not using steroids for at least 7 days prior to trial treatment (stereotactic brain radiation therapy to isolated brain metastases does not require washout period providing no steroids are required) With signs and/or symptoms of central nervous system cancers (e.g., tumors, metastases, leptomeningeal disease) as determined by their physician, medical records, or by a brain MRI, either at the time of enrollment or during the study period Has known active parenchymal central nervous system (CNS) metastases that are symptomatic, and/or more than one lesions, and/or their largest diameter is > 5-mm and/or require antiepileptic drugs or corticosteroids; patients with carcinomatous meningitis are also excluded; exceptions are: subjects with previously treated brain metastases provided they are stable (without evidence of progression by imaging) for at least 2 weeks prior to C11-AMT and any neurologic symptoms have returned to baseline, have no evidence of new or enlarging brain metastases, and are not using ongoing steroids for at least 7 days prior to C11-AMT; patients with active (i.e. not treated with stereotactic radiosurgery), single, asymptomatic, up to 5-mm in largest diameter brain metastases (measured either by brain magnetic resonance imaging [MRI] with IV contrast or head CT with IV contrast measured within 2 weeks prior to C11-AMT) are allowed Distant metastases Prior brain cancer Participants with known brain metastases will be excluded from this clinical trial Patients with known brain metastases should be excluded from this clinical trial Patients with a diagnosis of intra-axial brain tumor at initial diagnosis or patients with known treated brain tumors on follow-up with concern for imaging progression Evidence for hemorrhage within any of the brain metastases. Participants with known brain metastases should be excluded from this clinical trial Participants with known brain metastases should be excluded from this clinical trial Patient must meet at least one of the four following criteria regarding brain tumor diagnosis:\r\n* Histological diagnosis of a brain tumor\r\n* Histological diagnosis of systemic cancer and brain MR imaging suggestive of metastatic disease to the brain\r\n* Pre-operative brain MR imaging suggestive of a brain tumor\r\n* Radiographic diagnosis of brain tumor in an inoperable location (e.g., brainstem) Brain metastases AIM 3: Patients with either cutaneous, visceral or brain melanoma metastases Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Participants with clinically inactive brain metastases may be included in the study. Participants with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment (1 week for stereotactic radiotherapy) Untreated brain or CNS metastases or brain/CNS metastases that have progressed. Subjects with previously treated and clinically stable brain/CNS metastases and who are off all corticosteroids for ? 4 weeks are eligible. Subject has known history of brain metastases. Histologically or cytologically documented extensive disease. Brain metastases; must be asymptomatic or treated and stable off steroids and anti-convulsants for at least 1 month prior to study treatment. Participants with known uncontrolled brain metastases Known active central nervous system (CNS) metastases and/or carcinomatous meningitis; NOTE: subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for >= 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Brain metastases unless asymptomatic and not requiring steroids for at least 4 weeks prior to start of study treatment (Patients with SCLC or LCNEC of lung only must have CT or MRI of brain during screening, and if metastases found, must have radiotherapy with 14 day washout or stereotactic radiotherapy or radio surgery with 7 day washout) Patients must have been diagnosed with one of the following:\r\n* Primary brain tumor (glioma, glioblastoma [GBM] etc); or\r\n* Up to 10 brain metastases Patients must be scheduled to undergo standard brain cancer interventions:\r\n* Chemotherapy or targeted antiangiogenic therapy, in the case of primary brain tumor; or\r\n* Stereotaxic radiotherapy (SRS) or whole brain radiotherapy (WBRT), in the case of brain metastases Participants with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study Known brain metastases Patients with symptomatic brain metastases are excluded from this study. Known brain metastases All subjects with brain metastases, except those meeting the following criteria:\r\n* Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment \r\n* No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable)\r\n* Subjects must be either off steroids or on a stable or decreasing dose of =< 10 mg daily prednisone (or equivalent), excluding dexamethasone given as pre-treatment for trabectedin Active or progressing brain metastases Patients with known brain metastases Untreated brain metastases Clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with steroids may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 4 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment (2 weeks for stereotactic radiotherapy). Presence of gliomas and brain metastases only if neurologically stable and treated without ongoing requirement for corticosteroids for at least 2 weeks. Symptomatic, progressive or corticosteroids-requiring documented brain metastases or leptomeningeal disease involvement. Brain metastases allowed if asymptomatic, without edema, and not receiving corticosteroids or radiation The patient has a histologically confirmed solid tumor that is metastatic or unresectable for which standard measures do not exist or are no longer effective. (Patients with primary brain cancer or lymphoma are permitted. Patients with brain metastases are allowed if whole brain radiation was performed and is documented stable for ? 6 weeks) Has active brain metastases or leptomeningeal metastases. Participants with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. There must also be no requirement for high doses of systemic corticosteroids that could result in immunosuppression (greater than [>] 10 milligram per day [mg/day] prednisone equivalents) for at least 2 weeks prior to study drug administration. Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms Subjects with detectable cerebrospinal fluid malignant cells or brain metastases or with a history of cerebrospinal fluid malignant cells or brain metastases Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with primary brain tumors or primary tumors with central nervous system metastases as only location of disease. Controlled brain metastases are permitted Has active brain metastases or leptomeningeal metastases. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they have stable brain metastases and did not receive chemotherapy for metastatic breast cancer. Subjects with any evidence of distant metastases Participants must not have symptomatic brain metastases or brain metastases requiring steroids; asymptomatic brain metastases not requiring steroids are acceptable Brain metastases allowed if asymptomatic at study baseline. Patients with untreated brain metastases must not be on corticosteroids. If patients have neurological symptoms or signs due to CNS metastases, patients need to complete whole brain radiation or focal treatment at least 14 days before start of study treatment and be asymptomatic on stable or decreasing doses of corticosteroids at baseline. CNS tumor or clinically active brain metastases. Brain metastases have been treated. Patients with known active brain metastases or carcinomatous meningitis are excluded from this clinical trial; patients whose brain metastatic disease status has remained stable for >= 4 weeks following treatment of brain metastases are eligible to participate at the discretion of the principal investigator Participants with known brain metastases who have completed whole brain radiotherapy, stereotactic radiosurgery or complete surgical resection, will be eligible if they have remained clinically stable, asymptomatic, and off steroids for one month. Patients with brain metastases may participate if they have undergone appropriate treatment for the lesion(s), are at least two weeks post treatment without evidence for post-treatment progression, have no significant neurologic symptoms, and no longer require steroids for the reason of brain metastases Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable (i.e., without evidence of progression by repeat imaging), clinically stable and without requirement of steroid treatment for ?14 days prior to the first dose of study drug. Brain metastases that are untreated, symptomatic, or require therapy to control symptoms, as well as any history of radiation, surgery, or other therapy, including steroids, to control symptoms from brain metastases within 1 month (30 days) of enrollment. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks and, have no evidence of new or enlarging brain metastases and also are off steroids 3 days prior to dosing with study medication; stable brain metastases by this definition should be established prior to the first dose of pembrolizumab Symptomatic brain metastases Patients with known untreated and uncontrolled brain metastases are excluded. However, brain-imaging studies are not required for eligibility if the patient has no neurological signs or symptoms. Patient has a primary neoplasm of the brain or known uncontrolled metastases to the central nervous system (CNS). Patients with brain metastases are eligible, provided they have shown clinical and radiographically stable disease for at least 4 weeks after definitive therapy and have not used steroids for at least 4 weeks prior to first dose of PRN1371.