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 treatmentXx_NEWLINE_xXNo evidence of distant metastasesXx_NEWLINE_xXParticipants 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 administrationXx_NEWLINE_xXInclusion 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 seizuresXx_NEWLINE_xXHave 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.Xx_NEWLINE_xXPatients with any known brain or leptomeningeal metastases are excluded, even if treated.Xx_NEWLINE_xXNo evidence of distant metastasesXx_NEWLINE_xXPatients with known brain active and untreated metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients 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 treatmentXx_NEWLINE_xXPatients 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 daysXx_NEWLINE_xXPatients with brain metastases or primary brain tumors must have completed treatment, surgery or radiation therapy >= 4 weeks prior to start of treatmentXx_NEWLINE_xXPatients 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 registrationXx_NEWLINE_xXPatients 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 CohortXx_NEWLINE_xXProgressive 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 diseaseXx_NEWLINE_xXPatients 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 registrationXx_NEWLINE_xXPatients 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 ineligibleXx_NEWLINE_xXPatients 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 ineligibleXx_NEWLINE_xXPatients with no known brain metastasis must have baseline brain imaging within 12 weeks prior to study registration not demonstrating brain metastases ORXx_NEWLINE_xXPatients 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 allowedXx_NEWLINE_xXPatients 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)Xx_NEWLINE_xXPatients 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 drugsXx_NEWLINE_xXParticipants 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 asymptomaticXx_NEWLINE_xXNo current symptomatic, untreated, or uncontrolled brain metastases presentXx_NEWLINE_xXPrior radiotherapy for patients with brain metastases prior to enrollment is acceptable.Xx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXClinical or radiologic evidence of new, untreated, and/or progressive brain metastases prior to registration after induction systemic therapy.Xx_NEWLINE_xXPatients 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 registrationXx_NEWLINE_xXBrain metastasesXx_NEWLINE_xXAt 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 lesionXx_NEWLINE_xXPatients 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 as long as these were started at least 4 weeks prior to enrollment; patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 daysXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trial except as those described belowXx_NEWLINE_xXKnown symptomatic brain metastasesXx_NEWLINE_xXParticipants 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.Xx_NEWLINE_xXPatient has symptomatic brain metastases (i.e., metastases that are accompanied by neurological symptoms or that require treatment with corticosteroids)Xx_NEWLINE_xXPrimary brain cancers or active CNS metastases should be excluded from this clinical trialXx_NEWLINE_xXParticipants 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 treatmentXx_NEWLINE_xXParticipants with known untreated brain metastases are excluded from this clinical trialXx_NEWLINE_xXNo active brain metastasesXx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXSpinal cord compression or brain metastases unless asymptomatic, treated, stable, and not requiring steroids for at least 4 weeks before first dose of study drugXx_NEWLINE_xXPatients 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 monitorXx_NEWLINE_xXBrain metastases requiring steroidsXx_NEWLINE_xXBrain TumorsXx_NEWLINE_xXKnown brain metastases (unless previously treated and well controlled for a period of at least 3 months).Xx_NEWLINE_xXSymptomatic 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)Xx_NEWLINE_xXPrimary brain tumors or clinical evidence of active brain metastasisXx_NEWLINE_xXParticipants with known brain metastasesXx_NEWLINE_xXSpinal cord compression or brain metastases unless asymptomatic treated and stable and not requiring steroidsXx_NEWLINE_xXDistant metastasesXx_NEWLINE_xXParticipants with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients with symptomatic brain or bone metastasis are NOT eligible for participation; prior radiation and/or steroid therapy for brain or bone metastasis (mets) must be completed >= 2 weeks prior to study enrollmentXx_NEWLINE_xXKnown symptomatic brain metastases (NOTE: patients with treated epidural disease are allowed)Xx_NEWLINE_xX16. 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;Xx_NEWLINE_xXKnown 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.Xx_NEWLINE_xXAsymptomatic untreated brain metastases are allowed; symptomatic metastases that have undergone local therapy with radiation therapy (RT) or surgery and have not required an increase in steroid dose in prior 2 weeks are allowed; disease that has undergone local therapy is not considered measurable (for treatment phase)Xx_NEWLINE_xXHave no evidence of new or enlarging brain metastasesXx_NEWLINE_xXPatients with symptomatic uncontrolled brain metastases; a scan to confirm the absence of brain metastases is not required; patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 daysXx_NEWLINE_xXParticipants 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 eventsXx_NEWLINE_xXSubjects with treated brain metastases are eligible provided they meet the following criteria:Xx_NEWLINE_xXParticipants with known brain metastases should be excluded; screening for brain metastases with head imaging is not requiredXx_NEWLINE_xXSpinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatmentXx_NEWLINE_xXUncontrolled brain metastasesXx_NEWLINE_xXActive central nervous system (CNS) metastases; subjects must undergo a head computed tomography (CT) scan or brain magnetic resonance imaging (MRI) within 28 days prior to registration for protocol therapy to exclude brain metastases if symptomatic or without prior brain imagingXx_NEWLINE_xXCNS 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.Xx_NEWLINE_xXSubjects with symptomatic brain metastases, carcinomatous meningitis, spinal cord compression, or intractable back pain due to compression of destructive massXx_NEWLINE_xXKnown 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 steroidsXx_NEWLINE_xXLeptomeningeal disease or uncontrolled brain metastasis\r\n* NOTE: Metastases treated by surgery and/or radiotherapy such that patient is neurologically stable and off steroids >= 12 weeks prior to preregistration are eligibleXx_NEWLINE_xXFemales who are pregnant or breastfeeding. ? Patients who have active or stable brain metastases or who have a history of brain metastases.Xx_NEWLINE_xXUntreated or uncontrolled brain metastasis.Xx_NEWLINE_xXParticipants with symptomatic brain metastases that require active treatment are excludedXx_NEWLINE_xXKnown 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 physicianXx_NEWLINE_xXSubjects with brain metastasesXx_NEWLINE_xXAny current brain or subdural metastasesXx_NEWLINE_xXParticipants 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 treatmentXx_NEWLINE_xXPatients 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 enrollmentXx_NEWLINE_xXActive brain metastasesXx_NEWLINE_xXSome types of brain metastasesXx_NEWLINE_xXPatients may not have diagnosed brain metastasesXx_NEWLINE_xXCOHORT A: Previously untreated asymptomatic brain metastasesXx_NEWLINE_xXCOHORT D: 1-4 brain metastases (where stereotactic radiosurgery would be indicated)Xx_NEWLINE_xXWill need immediate local surgery or radiation for their brain metastasesXx_NEWLINE_xXSubject with known active CNS metastasis, except primary brain tumors. Subjects with asymptomatic brain metastases or spinal cord compression who have been treated, are considered stable, and have not received steroid doses > 10 mg/day of prednisolone equivalent to treat these conditions prior to consent may be included;Xx_NEWLINE_xXHave 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 for at least 4 weeks prior to the first dose of study medicationXx_NEWLINE_xXBrain metastases (brain imaging is not required)Xx_NEWLINE_xXPatients with brain metastases are allowed onto the study as long as patients have completed their treatment for brain metastasis, no longer require corticosteroids, and are asymptomatic; subjects with neurological symptoms should undergo a head computed tomography (CT) scan or brain magnetic resonance imaging (MRI) to exclude brain metastasis, at the discretion of the treating physicianXx_NEWLINE_xXFor 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.Xx_NEWLINE_xXSymptomatic metastatic brain or meningeal tumorsXx_NEWLINE_xXSymptomatic 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 treatmentXx_NEWLINE_xXParticipants with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXParticipants 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 eligibleXx_NEWLINE_xXPatients with symptomatic brain metastases; subjects with untreated brain metastasis =< 1 cm can be considered eligible if deemed asymptomatic by the investigator upon consultation with the medical monitor and do not require immediate radiation or steroids; subjects with brain metastasis that is treated and stable for 1 month may be considered eligible if they are asymptomatic and on stable dose of steroids or if they do not require steroids following successful local therapyXx_NEWLINE_xXActive or untreated brain metastases or spinal cord compression\r\n* A scan to confirm the absence of brain metastases is not required\r\n* Patients with treated brain metastases or spinal cord compression are eligible if they have minimal neurologic symptoms and evidence of stable disease (for at least 1 month) or response on follow-up scan; 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 treatmentXx_NEWLINE_xXUntreated or clinically active melanoma brain metastases.Xx_NEWLINE_xXSubjects 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.Xx_NEWLINE_xXPatients with uncontrolled brain metastases.Xx_NEWLINE_xXUncontrolled brain metastasesXx_NEWLINE_xXBrain metastases.Xx_NEWLINE_xXPatients 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 symptomsXx_NEWLINE_xXPartial brain radiotherapy (i.e. =< 40% of total brain volume) within the last 2 weeksXx_NEWLINE_xXWhole brain radiotherapy within the last 6 months or partial brain radiotherapy exceeding > 40% of total brain volume within the last 6 monthsXx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXIf 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.Xx_NEWLINE_xXUncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases; asymptomatic or treated brain metastases are acceptableXx_NEWLINE_xXBrain 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 drugXx_NEWLINE_xXPrimary brain tumor or active brain metastasisXx_NEWLINE_xXHas 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).Xx_NEWLINE_xXHistory 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 imagingXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients with metastasesXx_NEWLINE_xXPatients 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 investigatorXx_NEWLINE_xXParticipants 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.Xx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXActive or previous brain metastasisXx_NEWLINE_xXParticipants must have a diagnosis of brain metastases for which SRS is indicated, as determined by a radiation oncologistXx_NEWLINE_xXParticipants 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 permittedXx_NEWLINE_xXParticipants with known brain metastases or evidence of leptomeningeal involvement are eligible only if these lesions are treated and both clinically and radiographically stable for at least four weeks; patients are eligible if they are being treated with a stable dosage of steroids/anticonvulsants, requiring no dose increase for 4 weeksXx_NEWLINE_xXParticipants 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 studyXx_NEWLINE_xXParticipants who have received prophylactic cranial radiation for prevention of brain metastasesXx_NEWLINE_xXParticipants with > 6 definitive lesions consistent with brain metastasesXx_NEWLINE_xXActive brain metastases or leptomeningeal metastasesXx_NEWLINE_xXParticipant has untreated brain or meningeal metastases.Xx_NEWLINE_xXSubjects with brain metastasisXx_NEWLINE_xXSubject 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 asymptomaticXx_NEWLINE_xXPatient has spinal cord compression or symptomatic brain metastases.Xx_NEWLINE_xXBrain metastases that:Xx_NEWLINE_xXOr 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.Xx_NEWLINE_xXPatients 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 administrationXx_NEWLINE_xXKnown symptomatic brain metastases requiring ?10 mg/day of prednisolone (or its equivalent).Xx_NEWLINE_xXKnown intracranial metastasesXx_NEWLINE_xXENROLLMENT 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 investigatorXx_NEWLINE_xXPatients with known symptomatic brain metastases requiring steroids in part 1 or 2Xx_NEWLINE_xXFor 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)Xx_NEWLINE_xXHistory 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 eventsXx_NEWLINE_xXKnown 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 medicationsXx_NEWLINE_xXParticipants 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 permittedXx_NEWLINE_xXPresence of untreated brain metastasisXx_NEWLINE_xXSubjects 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 CNSXx_NEWLINE_xXBrain metastases with risk of mass effect that would contraindicate lumbar punctureXx_NEWLINE_xXThose with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXBrain lesions or intracranial abnormalities at risk for bleeding, by history or radiologic imaging (e.g., active metastases).Xx_NEWLINE_xXKnown 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 physicianXx_NEWLINE_xXSubjects with known symptomatic brain metastases or leptomeningeal metastasesXx_NEWLINE_xXParticipants 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 studyXx_NEWLINE_xXParticipants with asymptomatic CNS metastases with previous or concomitant brain deficiencies, as defined in the protocolXx_NEWLINE_xXPatients 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 investigatorXx_NEWLINE_xXSymptomatic 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 treatmentXx_NEWLINE_xXKnown 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 registrationXx_NEWLINE_xXSubjects with known brain metastasis are excluded from this study; patients with suspected brain metastasis must have brain imaging (either magnetic resonance imaging [MRI] brain or computed tomography [CT] brain with contrast) prior to enrollmentXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients 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 investigatorXx_NEWLINE_xXPatients with brain metastases unless they meet the criteriaXx_NEWLINE_xXKnown 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 excludedXx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXhave no evidence of new or enlarging brain metastases, andXx_NEWLINE_xXAt least one measurable lesion per RANO-BM (Response Assessment in Neuro-Oncology Brain Metastases) Criteria for brain metastasisXx_NEWLINE_xXPatients who have a single, operable brain metastasisXx_NEWLINE_xXRecurrent brain metastasesXx_NEWLINE_xXPrior WBRT for newly diagnosed brain metastasesXx_NEWLINE_xXPatients 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 treatmentXx_NEWLINE_xXActive or untreated brain metastasesXx_NEWLINE_xXThe 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 eligibilityXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trial; a scan to confirm the absence of brain metastasis is not requiredXx_NEWLINE_xXNo history of intracranial brain metastasisXx_NEWLINE_xXSymptomatic or uncontrolled brain metastasesXx_NEWLINE_xXKnown 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 eventsXx_NEWLINE_xXPatients with known brain metastasesXx_NEWLINE_xXSpinal cord compression or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study treatment.Xx_NEWLINE_xXPatients 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 corticosteroidsXx_NEWLINE_xXPatients with untreated symptomatic brain metastases may be eligible if symptoms do not require urgent surgery or radiation, and no steroids are necessaryXx_NEWLINE_xXUncontrolled 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.).Xx_NEWLINE_xXPatient 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 permittedXx_NEWLINE_xXParticipants 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 permittedXx_NEWLINE_xXUntreated 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)Xx_NEWLINE_xXParticipants 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.Xx_NEWLINE_xXPatients 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)Xx_NEWLINE_xXLargest brain metastases volume measures less than 14.15 cc^3Xx_NEWLINE_xXIf they have brain metastases located in the brain stem (including midbrain, pons, or medulla)Xx_NEWLINE_xXParticipants with known brain metastases should be excludedXx_NEWLINE_xXPatients 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)Xx_NEWLINE_xXPatients with brain metastases will be excluded if metastases have been symptomatic or actively treated within 4 weeks prior to enrollmentXx_NEWLINE_xXSubjects with brain metastases are eligibleXx_NEWLINE_xXPatients 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 daysXx_NEWLINE_xXSymptomatic or untreated leptomeningeal or brain metastases or spinal cord compression; treated brain metastases must have been stable for at least 1 month and require treatment with less than 10 mg/day prednisone equivalent for at least two weeks prior to study drug administrationXx_NEWLINE_xXPatients 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 eventsXx_NEWLINE_xXPatients 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 registeredXx_NEWLINE_xXPatients with uncontrolled brain metastases. Existing brain metastases must have been previously treated and currently stable.Xx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXPatients 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 aboveXx_NEWLINE_xXPatients 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 treatmentXx_NEWLINE_xXSubject 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)Xx_NEWLINE_xXPatients 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 enrollmentXx_NEWLINE_xXSymptomatic metastatic brain or meningeal tumorsXx_NEWLINE_xXThe presence of known brain metastasesXx_NEWLINE_xXSymptomatic metastatic brain or meningeal tumorsXx_NEWLINE_xXUntreated or symptomatic brain metastases requiring corticosteroid therapy (no corticosteroid use for this purpose in the preceding 4 weeks)Xx_NEWLINE_xXBulky intracranial metastatic disease with shift of midline structures or progressive brain metastasis such that ongoing therapy for these brain metastasis is required at the time of enrollment.Xx_NEWLINE_xXPatients 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 investigatorXx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXPlanning of any brain local treatment (including but not limited to surgery, stereotactic radiosurgery, whole brain radiation, intrathecal chemotherapy) following the administration of the first dose of study drug.Xx_NEWLINE_xXBrain 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 CriteriaXx_NEWLINE_xXPatients with known brain metastases will be excluded from this clinical trialXx_NEWLINE_xXPatients with known brain metastases will be excluded from this clinical trialXx_NEWLINE_xXNo active intracranial metastasesXx_NEWLINE_xXPresence 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 treatmentXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXPatients who have had brain metastases unless they meet the criteria.Xx_NEWLINE_xXPatients with untreated known brain metastases, or treated brain metastases that are clinically unstableXx_NEWLINE_xXKnown metastases in the brain or active epidural disease (NOTE: patients with treated epidural disease are allowed)Xx_NEWLINE_xXPatient has known brain metastases,Xx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXActive 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.Xx_NEWLINE_xXPatients with active brain metastases are not eligible; patients with brain metastases that have been treated and stable for > 30 days following treatment will be eligibleXx_NEWLINE_xXPatients 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 participateXx_NEWLINE_xXNo active brain metastasis; previously surgically treated or irradiated lesions are allowed if not clinically activeXx_NEWLINE_xXPatients 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 investigatorXx_NEWLINE_xXSubjects with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients with known brain metastasesXx_NEWLINE_xXPresence or history of brain metastases.Xx_NEWLINE_xXHistory of brain metastasesXx_NEWLINE_xXPatients can have concomitant brain metastases as long as they do not require active treatment or have been treatedXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients with known brain metastases unless treated with an appropriate modality with no evidence of progression/recurrence for > 3 monthsXx_NEWLINE_xXNo symptomatic brain metastasis; (note: patients with treated brain metastasis must be off steroids or on tapering or stable doses of steroids and have completed radiation at least 14 days prior to registration for protocol therapy)Xx_NEWLINE_xXPatients 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 therapyXx_NEWLINE_xXAll 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).Xx_NEWLINE_xXSubjects 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)Xx_NEWLINE_xXSymptomatic 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)Xx_NEWLINE_xXSubjects 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 eligibleXx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXPatients 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 as long as 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 daysXx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXHas 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 stabilityXx_NEWLINE_xXSymptomatic or clinically active brain metastasesXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXAt least one measurable lesion per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) Criteria for brain metastasisXx_NEWLINE_xXPrior systemic therapy is allowed after diagnosis of brain metastases provided that restaging MRI shows measurable intracranial diseaseXx_NEWLINE_xXHistory of prior brain metastasesXx_NEWLINE_xXConcurrent brain-directed therapyXx_NEWLINE_xXBrain 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.Xx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPresence of untreated brain metastases; if patients have had previous treatment for the brain metastasis, an MRI or CT scan of the brain must confirm the stabilization of the brain metastasis for more than 2 monthsXx_NEWLINE_xXParticipants must not have active brain metastases or leptomeningeal metastasesXx_NEWLINE_xXKnown 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 excludedXx_NEWLINE_xXPatients who have metastases to the brain.Xx_NEWLINE_xXThe patient has active brain metastasesXx_NEWLINE_xXKnown 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 eventsXx_NEWLINE_xXA 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, and are asymptomaticXx_NEWLINE_xXHistory of, or current brain metastasesXx_NEWLINE_xXKnown brain metastasisXx_NEWLINE_xXUntreated 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)Xx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXUncontrolled 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)Xx_NEWLINE_xXBrain metastases or spinal cord compression unless asymptomatic and not requiring steroids for at least 14 days prior to start of study treatmentXx_NEWLINE_xXKnown brain metastases who are clinically unstableXx_NEWLINE_xXFor 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 eligibleXx_NEWLINE_xXHas 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)Xx_NEWLINE_xXRadiographically confirmed solid tumor brain metastasesXx_NEWLINE_xXA diagnostic magnetic resonance imaging (MRI) brain or computed tomography (CT) head demonstrating the presence of 1-4 solid tumor brain metastases and lesion to be resected no more than 5 cm in any direction, performed within 30 days prior to stereotactic radiosurgery. If multiple lesions are present, then the total brain metastases volume can be no more than 30 cm^3 excluding the lesion to be resectedXx_NEWLINE_xXPatients with more than 4 brain metastases on MRI brain or CT headXx_NEWLINE_xXCOHORT 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 allowedXx_NEWLINE_xXCOHORT 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 allowedXx_NEWLINE_xXCOHORT 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 allowedXx_NEWLINE_xXSubjects 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.Xx_NEWLINE_xXSubjects with primary brain cancers or active CNS metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients 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 studyXx_NEWLINE_xXFor 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 weeksXx_NEWLINE_xXPatient has symptomatic brain or CNS metastasesXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients with known symptomatic brain metastases requiring steroidsXx_NEWLINE_xXPatients must have a history of brain metastases that are non-progressing.Xx_NEWLINE_xXPatients 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 imagingXx_NEWLINE_xXKnown, untreated brain metastasis. Patients with signs or symptoms of brain metastasis must have a CT or MRI performed within 4 weeks prior to randomization to specifically exclude the presence of radiographically-detected brain metastasesXx_NEWLINE_xXParticipants with symptomatic known brain metastases < 4 weeks from radiation treatment should be excluded from this clinical trialXx_NEWLINE_xXPatients 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 metastasesXx_NEWLINE_xXPatients who have known leptomeningeal metastases or untreated or symptomatic brain metastases; treated, asymptomatic brain metastasis can be includedXx_NEWLINE_xXHistory of brain metastases or who currently have treated or untreated brain metastasesXx_NEWLINE_xXMetastases in the brainXx_NEWLINE_xXPrimary brain or spine tumor are eligible, including tumors with metastases, multiple lesionsXx_NEWLINE_xXARM 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 enrollmentXx_NEWLINE_xXPatients with “treated and stable” brain lesions of a duration of > 4 weeks may be enrolledXx_NEWLINE_xXBrain 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 monthsXx_NEWLINE_xXPatients 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 enrollmentXx_NEWLINE_xXPatients with no history of CNS disease will not require a repeat MRI brain unless they have symptoms to suggest new brain metastasesXx_NEWLINE_xXParticipants with active brain metastasesXx_NEWLINE_xXNote: 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 treatmentXx_NEWLINE_xXKnown 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 excludedXx_NEWLINE_xXPatients 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) treatmentXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients with known symptomatic brain metastasis; subjects with controlled brain metastasis (no radiographic progression at least 4 weeks following radiation and/or surgical treatment and no neurological signs or symptoms) will be allowedXx_NEWLINE_xXPatients 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 asymptomaticXx_NEWLINE_xXSubjects 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.Xx_NEWLINE_xXSubjects with active brain metastases.Xx_NEWLINE_xXPatients 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 stableXx_NEWLINE_xXPatients with untreated brain metastasis; patients with metastatic lesions to the brain may be enrolled after completing stereotactic radiosurgery or whole brain radiation (may enroll 14 days after treatment and must be off corticosteroids for at least 14 days prior to the start of study treatmentXx_NEWLINE_xXPatients 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).Xx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXUntreated brain metastases, symptomatic brain metastases, brain metastases requiring steroids to manage symptoms, or treatment for brain metastases within 8 weeks prior to randomization;Xx_NEWLINE_xXHistory of uncontrolled brain metastasis unless:Xx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXHas 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).Xx_NEWLINE_xXPatients with active brain metastases should be excluded from this clinical trial.Xx_NEWLINE_xXPatients with known brain metastases, as progressive neurologic dysfunction may develop that would confound the evaluation of neurologic and other adverse eventsXx_NEWLINE_xXPatients 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 administrationXx_NEWLINE_xXParticipants 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.Xx_NEWLINE_xXKnown 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 metastasesXx_NEWLINE_xXBrain 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 statusXx_NEWLINE_xXPatients 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 steroidsXx_NEWLINE_xXSymptomatic or untreated leptomeningeal or brain metastases or spinal cord compression; treated brain metastases are allowed as long as they are stable for at least 28 days post-treatmentXx_NEWLINE_xXPatient must be scheduled to undergo treatment with WBRT to manage the brain metastasesXx_NEWLINE_xXPatient does not have any brain metastases in the genuXx_NEWLINE_xXPatients receiving prior stereotactic radiosurgery (SRS) for brain metastases are eligibleXx_NEWLINE_xXPatients with brain metastases in the genuXx_NEWLINE_xXPatients 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 excludedXx_NEWLINE_xXPatients 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 yearXx_NEWLINE_xXThe 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 tumorXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients 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) treatmentXx_NEWLINE_xXIf 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 metastasesXx_NEWLINE_xXUntreated brain metastasesXx_NEWLINE_xXPresence or history of brain metastasesXx_NEWLINE_xXParticipants with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients with known brain metastases will be excluded from this clinical trialXx_NEWLINE_xXKnown 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 studyXx_NEWLINE_xXBrain 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.Xx_NEWLINE_xXSymptomatic brain metastasis requiring corticosteroidsXx_NEWLINE_xXPhase 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 enrollmentXx_NEWLINE_xXPhase 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 enrollmentXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXPrevious radiation to the brain, including WBRT or brain radiosurgeryXx_NEWLINE_xXPatients with previously untreated brain metastases should be excluded; patients with treated and stable (> 4 weeks) brain metastases may be eligible for enrollmentXx_NEWLINE_xXUntreated brain metastases, if not planned to be treated in this course of radiation therapyXx_NEWLINE_xXSymptomatic brain metastases requiring immediate local interventions such as craniotomy or stereotactic radiosurgery (SRS)Xx_NEWLINE_xXUntreated brain metastasesXx_NEWLINE_xXKnown 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 restagingXx_NEWLINE_xXAll 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)Xx_NEWLINE_xXParticipants 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 stableXx_NEWLINE_xXParticipants with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXDocumented 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 abemaciclibXx_NEWLINE_xXBrain metastases or a history of brain metastasesXx_NEWLINE_xXPatients 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 excludedXx_NEWLINE_xXPatients 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 administrationXx_NEWLINE_xXSubjects with radiographically stable treated brain metastases are eligible but must not have been on steroid therapy for at least 4 weeksXx_NEWLINE_xXKnown untreated or symptomatic brain metastasesXx_NEWLINE_xXBrain metastases unless previously treated and well controlled for at least 3 monthsXx_NEWLINE_xXPatients with known or suspected brain metastasisXx_NEWLINE_xXSymptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroidsXx_NEWLINE_xXPatients with known brain metastases will be excluded from this clinical trialXx_NEWLINE_xXPatients 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 eventsXx_NEWLINE_xXUncontrolled brain metastases; patients treated with radiation >= 4 weeks prior with follow up imaging showing control are eligibleXx_NEWLINE_xXPatients 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 enrollmentXx_NEWLINE_xXSymptomatic metastatic brain or meningeal tumorsXx_NEWLINE_xXPrimary brain tumors or known brain metastasis unless clinically stable and on stable or reducing doses of steroids.Xx_NEWLINE_xXPreviously treated (surgery and/or radiation therapy) or untreated brain metastases are eligible, provided that patients are asymptomatic and not requiring escalating doses of corticosteroidsXx_NEWLINE_xXPresence of symptomatic brain metastases or brain metastases requiring escalating doses of corticosteroids to control neurological symptomsXx_NEWLINE_xXPatients 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 trialXx_NEWLINE_xXTreated stable brain metastases are allowed, as long as patient does not require steroids or anti-seizure medicationsXx_NEWLINE_xXPatient with brain metastasis must have had treatment of their brain metastasis completed at least 1 day prior to enrollment and be on stable dose of steroids or off steroids at the time of enrollmentXx_NEWLINE_xXPatients with known extrathoracic metastases, including brain metastases, or known malignant pleural or pericardial effusionXx_NEWLINE_xXPatients with treated, stable, and asymptomatic brain metastases are eligibleXx_NEWLINE_xXUntreated, progressing, or symptomatic brain metastasesXx_NEWLINE_xXSymptomatic brain metastases or leptomeningeal (LM) disease requiring corticosteroids for symptom management; asymptomatic brain metastases or LM will be allowed on studyXx_NEWLINE_xXMetastases to brain per prior clinical evaluation;Xx_NEWLINE_xXActive 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)Xx_NEWLINE_xXParticipants with history of brain metastases who have not shown clinical and radiographic stable disease for at least 28 days after definitive therapy.Xx_NEWLINE_xXPatients 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 enrolledXx_NEWLINE_xXAll 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)Xx_NEWLINE_xXHave had prior radiation therapy to the brain or prior treatment for their brain tumor (except prior biopsy or subtotal resection)Xx_NEWLINE_xXSubjects with brain metastasesXx_NEWLINE_xXPatients 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)Xx_NEWLINE_xXBrain metastases are allowed, as long as they are stable and do not require treatment with anticonvulsants or escalating doses of steroidsXx_NEWLINE_xXHave 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 escalating corticosteroids nor anti-convulsant medications for at least 4 weeks prior to the first dose of study medicationXx_NEWLINE_xXSubjects 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 treatedXx_NEWLINE_xXPatient with a known history or evidence of brain metastasesXx_NEWLINE_xXAll 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)Xx_NEWLINE_xXUnresectable metastasesXx_NEWLINE_xXPatients with uncontrolled brain metastases; patients with brain metastases must be asymptomatic and off corticosteroids for at least one weekXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXNo known or suspected brain metastases (NOTE: patients with treated epidural disease are allowed)Xx_NEWLINE_xXSpinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 4 weeks prior to start of study treatmentXx_NEWLINE_xXSubjects with detectable cerebrospinal fluid malignant cells or known brain metastases, or with a history of cerebrospinal fluid malignant cells or brain metastases.Xx_NEWLINE_xXParticipants with known brain metastases from solid tumors should be excluded from this clinical trialXx_NEWLINE_xXSymptomatic or unstable brain metastases.Xx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients with active brain metastases; a scan to confirm the absence of brain metastases is not required for asymptomatic patientsXx_NEWLINE_xXUntreated brain metastasis(es) that may be considered activeXx_NEWLINE_xXHas 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.Xx_NEWLINE_xXPatients 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 participateXx_NEWLINE_xXPatients 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 weeksXx_NEWLINE_xXPrior whole brain irradiationXx_NEWLINE_xXSymptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroidsXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients 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)Xx_NEWLINE_xXPatients with known brain metastases are excluded from this clinical trial; patients with primary brain tumors amenable to surgery are allowed on this protocolXx_NEWLINE_xXPatients with known brain metastasesXx_NEWLINE_xXKnown active and/or untreated brain metastasesXx_NEWLINE_xXSymptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroidsXx_NEWLINE_xXPatients with symptomatic extrahepatic metastasesXx_NEWLINE_xXClinical stability of brain metastases for at least 4 weeks prior to first day of study therapy.Xx_NEWLINE_xXAll 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)Xx_NEWLINE_xXSymptomatic brain metastasesXx_NEWLINE_xXSymptomatic metastatic brain or meningeal tumorsXx_NEWLINE_xXPatients may have metastases, with newly identified peripheral metastasesXx_NEWLINE_xXPatients 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 drugsXx_NEWLINE_xXSubjects 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 diseaseXx_NEWLINE_xXPatients 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 eventXx_NEWLINE_xXSubjects with known or suspected brain metastasis, or brain as the only site of disease are excluded with the following exceptionsXx_NEWLINE_xXPatients 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 treatmentXx_NEWLINE_xXSubjects 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.Xx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXPatients 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 lessXx_NEWLINE_xXActive/untreated brain metastasis; whole brain radiation or gamma knife radiosurgery performed less than 4 weeks prior to first administration of study drug; previously treated brain metastasis allowed as long as not requiring steroids and stable on imaging at least 4 weeks after completing radiation therapyXx_NEWLINE_xXSymptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroidsXx_NEWLINE_xXUntreated 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 metastasesXx_NEWLINE_xXActive/untreated brain metastasis: whole brain radiation or gamma knife radiosurgery performed less than 4 weeks prior to first administration of study drug; previously treated brain metastasis allowed as long as not requiring steroids and stable on imaging at least 4 weeks after completing radiation therapyXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients 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 malformationXx_NEWLINE_xXSymptomatic 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 eligibleXx_NEWLINE_xXHave no known metastasesXx_NEWLINE_xXBrain metastases unless asymptomatic, stable and not requiring steroids for at least 2 weeksXx_NEWLINE_xXPreviously treated brain metastases (surgery and/or radiation therapy) are eligible, provided that patients are asymptomatic and not requiring corticosteroidsXx_NEWLINE_xXBrain metastasis allowed if previously treated, stable and off steroids for a minimum of 56 daysXx_NEWLINE_xXPatients 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) symptomsXx_NEWLINE_xXBrain metastases or spinal cord compression unless asymptomatic, treated and stable off steroids and anti-convulsants for at least 3 monthsXx_NEWLINE_xXActive brain metastases (e.g. stable for < 4 weeks, no adequate previous treatment with radiotherapy, symptomatic, requiring treatment with anti-convulsants; dexamethasone therapy will be allowed if administered as stable dose for at least one month before registration)Xx_NEWLINE_xXSymptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroidsXx_NEWLINE_xXPatients with symptomatic uncontrolled brain metastases are excluded; (patients with stable treated or asymptomatic untreated brain metastasis not requiring glucocorticoids are allowed)Xx_NEWLINE_xXPostoperative patients with resected brain metastases are eligibleXx_NEWLINE_xXGreater than 10 brain metastases; excluding previously treated and stable brain metastasesXx_NEWLINE_xXSymptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroidsXx_NEWLINE_xXPatients with brain metastases.Xx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXHistory or evidence of brain metastasesXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients with brain metastasis that have been treated with definitive surgery or radiation and have been clinically stable for 3 months are eligibleXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients with untreated brain metastasis are excluded; patients with a prior history of brain metastasis are eligible if they have received prior brain radiation, have improved or stable intracranial disease for at least 3 months after completion of last course of radiation, and are not taking corticosteroids for treatment of brain metastasis; patients with a prior history of brain metastases who meet other eligibility criteriaXx_NEWLINE_xXPatients with known brain metastasesXx_NEWLINE_xXPrior 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 administrationXx_NEWLINE_xXSymptomatic or untreated brain metastasesXx_NEWLINE_xXParticipants with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients with known brain metastases should be excludedXx_NEWLINE_xXOne to 4 untreated metastatic brain lesionsXx_NEWLINE_xXPatients 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 excludedXx_NEWLINE_xXKnown 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 metastasesXx_NEWLINE_xXPHASE 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 allowedXx_NEWLINE_xXPHASE 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 allowedXx_NEWLINE_xXEvidence of distant metastasesXx_NEWLINE_xXMore than one brain metastasis (qualifying measurable brain lesions are any contrast enhancing metastases identifiable by the physician)Xx_NEWLINE_xXPatients 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 brainXx_NEWLINE_xXPatients with brain metastases involving the brainstem or chiasmXx_NEWLINE_xXKnown brain metastases or spinal cord compressionXx_NEWLINE_xXPatients with treated and clinically stable brain metastases are allowedXx_NEWLINE_xXSymptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroidsXx_NEWLINE_xXFor subjects in cohort 2 (small cell malignancies of non-pulmonary origin), confirmation of no brain metastases via imagingXx_NEWLINE_xXSubjects 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 eligibleXx_NEWLINE_xXPatients 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 drugsXx_NEWLINE_xXPatients with both brain and spine metastases will be excluded from the trialXx_NEWLINE_xXSubject has known brain metastases; presence of brain metastases should be excluded from this clinical trialXx_NEWLINE_xXSymptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroidsXx_NEWLINE_xXPrimary 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)Xx_NEWLINE_xXActive uncontrolled or symptomatic brain metastases; previously treated and clinically stable, as per investigator’s judgment, brain metastases are permittedXx_NEWLINE_xXKnown 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 drugXx_NEWLINE_xXKnown brain metastases; patients with known brain metastases must be excluded from this clinical trialXx_NEWLINE_xXMetastatic melanoma or non-squamous NSCLC with untreated brain metastasesXx_NEWLINE_xXA 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 treatmentXx_NEWLINE_xXSymptomatic brain metastases; any neurologic symptoms present must have resolved with local therapy by the time of administration of study drugXx_NEWLINE_xXPatients with brain metastases for whom complete surgical resection is clinically appropriateXx_NEWLINE_xXBrain metastases unless previously treated and well controlled for at least 3 monthsXx_NEWLINE_xXSubjects 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.Xx_NEWLINE_xXClinically 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 enrollmentXx_NEWLINE_xXThe subject has active brain metastases or epidural diseaseXx_NEWLINE_xXAll brain metastases must be outside the brain stem (midbrain, pons and medulla)Xx_NEWLINE_xXPatient must have 10 or less brain metastasesXx_NEWLINE_xXSymptomatic 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)Xx_NEWLINE_xXBrain 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 doseXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients 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 eventsXx_NEWLINE_xXPatients with known brain metastases or leptomeningeal metastases should be excluded from this clinical trial; patients with other extrapleural metastases are included in this studyXx_NEWLINE_xXPatients 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 permittedXx_NEWLINE_xXSymptomatic or untreated CNS metastases or spinal cord compression. Brain metastasis must be stable with verification by imaging .Xx_NEWLINE_xXPatients 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 administrationXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXKnown parenchymal brain metastasisXx_NEWLINE_xXSymptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroidsXx_NEWLINE_xXThe 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 diseaseXx_NEWLINE_xXPrior whole brain irradiationXx_NEWLINE_xXCERITINIB EXCLUSION CRITERIA: Known symptomatic brain metastases or on unstable/increasing doses of steroid\r\n* Patients with asymptomatic brain metastases may be enrolled at the discretion of the sponsor as long as the patient is stable or has received treatment by a focal approach for brain metastases (e.g., radiation at least 2 weeks prior to starting ceritinib, or fully healed from neurosurgery)\r\n* Patients requiring seizure prophylaxis must be taking non-enzyme-inducing anti-epileptic drugs (non-EIAED); if patients were previously on EIAEDs and these have been discontinued, they must be discontinued for at least 1 weeks prior to capmatinib administration; if patients require an antiepileptic medication, then a CYP3A4 non-EIAED can be used such as levetiracetam, valproic acid, gabapentin, topiramate or lacosamide\r\n* Moderate inducers of CYP3A, CYP3A4, or CYP3A4/5 such as dexamethasone or other glucocorticoids may be used at the discretion of the Investigator; patients requiring steroid must be at a stable or decreasing for at least 5 days prior to study drug administrationXx_NEWLINE_xXREGORAFENIB 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 administrationXx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXKnown parenchymal brain metastasisXx_NEWLINE_xXSubjects 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.Xx_NEWLINE_xXBrain metastases and/or spinal cord compression untreated with surgery and/or radiotherapy, and without clinical imaging evidence of stable disease for 14 days or longer; Subjects requiring steroids within 4 weeks prior to start of study treatment will be excluded;Xx_NEWLINE_xXPatients 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 registrationXx_NEWLINE_xXNo evidence of distant metastasesXx_NEWLINE_xXBrain metastases or spinal cord compression unless the patient's condition is stable and off steroids for at least 14 days prior to the start of study treatment. Patients with suspected or known brain metastases at screening should have an MRI (preferred)/CT, preferably with IV contrast to access baseline disease status.Xx_NEWLINE_xXPatients will have no more than 4 distinct lesions within the brain; at least 1 lesion has been recommended for surgical removal based on size, symptomology, or regional mass effect on the brainXx_NEWLINE_xXMore than four additional diagnosed brain metastasesXx_NEWLINE_xXHave a history of or current evidence of intracranial disease; patients with brain metastases must be excluded from this clinical trialXx_NEWLINE_xXProgressive, symptomatic untreated brain metastasesXx_NEWLINE_xXPrior whole brain irradiationXx_NEWLINE_xXUntreated brain metastasis that may be considered activeXx_NEWLINE_xXAre symptomatic or have uncontrolled brain metastases, leptomeningeal disease, or spinal cord compression not definitively treated with surgery or radiation (brain metastases that are stable and asymptomatic, either treated or untreated, will be allowed)Xx_NEWLINE_xXNewly dignosed or active brain metastasisXx_NEWLINE_xXHas 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.Xx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients 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 administrationXx_NEWLINE_xXPatients 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 weeksXx_NEWLINE_xXMust not have untreated brain metastasesXx_NEWLINE_xXPrior whole brain irradiationXx_NEWLINE_xXBrain metastases or spinal cord compression unless asymptomatic, treated and stable off steroids and anti-convulsants for at least 30 daysXx_NEWLINE_xXPatients with known brain metastasesXx_NEWLINE_xXKnown 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 interventionXx_NEWLINE_xXSubjects 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 enrolledXx_NEWLINE_xXUntreated brain metastases, treated brain metastases that are not stable, leptomeningeal disease, or seizures uncontrolled with standard medical therapyXx_NEWLINE_xXPHASE 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 indicatedXx_NEWLINE_xXPHASE 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 indicatedXx_NEWLINE_xXPatients may have treated and stable brain metastases; they must be off steroids and must have had stable brain metastases for at least 6 monthsXx_NEWLINE_xXSubject 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)Xx_NEWLINE_xXSubjects with brain metastases should be excluded from this clinical trial unless all the metastasis are treated surgically or radio-surgicallyXx_NEWLINE_xXMeningeal 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 therapyXx_NEWLINE_xXPatients 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 allowedXx_NEWLINE_xXSubject must have cytologically or histologically confirmed malignancy (this is the original malignancy, not the brain metastases); the largest measurable brain metastasis must be at least 1.0 cm in short axis dimensionXx_NEWLINE_xXPatients 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 drugXx_NEWLINE_xXSymptomatic brain metastasisXx_NEWLINE_xXSubjects with known metastasesXx_NEWLINE_xXPatients with symptomatic or recurrent brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients 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)Xx_NEWLINE_xXPatients with known, untreated or progressive brain metastases will be excluded from this clinical trialXx_NEWLINE_xXSymptomatic and/or untreated Brain MetastasesXx_NEWLINE_xXBrain 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 permittedXx_NEWLINE_xXPatients must have 1-5 brain metastases totalXx_NEWLINE_xXUntreated 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 treatmentXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXCurrent 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 metastasesXx_NEWLINE_xXGliomas are excluded, as well as any history of brain metastases, seizures or underlying brain injuryXx_NEWLINE_xXKnown 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 C1D1Xx_NEWLINE_xXPresence of brain metastasesXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients with uncontrolled brain metastases; patients with brain metastases must be asymptomatic and off corticosteroids for at least one weekXx_NEWLINE_xXParticipants must have stable or responding systemic disease to TKI (no evidence of progression) on the most recent staging studies; the required staging studies are: (1) a re-staging computed tomography (CT) scan of the chest +/- abdomen with intravenous (IV) contrast (unless medically contraindicated) within 2 months of study enrollment; and (2) in patients with known brain metastasis, or to investigate patients with new onset of neurologic symptoms that may suggest metastasis to the brain, brain magnetic resonance imaging (MRI) with gadolinium, or head CT scan with IV contrast will be required within 2 months of study enrollment; the complete extent of the current residual systemic disease must be deemed amenable to SBRT as per review of imaging studies by a radiation oncologist involved in this trial; this will be based on the following criteria:\r\n* Lung: 1-3 lesions (including the primary) of maximum size 5 cm in longest diameter; a minimum size 1 cm in the longest diameter is recommended; (patients with a malignant pleural effusion prior to the start of TKI therapy will be considered eligible for SBRT if there is complete radiographic resolution of the effusion while on systemic therapy)\r\n* Spine: bone lesions must be limited to the spine; a maximum of 2 spinal metastases will be considered for SBRT, with each site spanning 1-3 vertebral bodies; a minimum size of 1 cm in longest diameter is recommended; SBRT may target sclerotic lesions that persist following TKI therapy\r\n* Gastrointestinal (GI): 1-4 liver metastases of maximum size 5 cm in longest diameter and/or 1-2 adrenal metastases of maximum 4 cm size in longest diameter; a minimum size of 1 cm in longest diameter is recommended\r\n* In addition:\r\n* Central nervous system (CNS): 1-4 brain metastases of maximum size 3cm in longest diameter; however, these should be treated with standard-of-care stereotactic radiosurgery (SRS) and will not be defined as target lesions for purposes of this protocol; there is no minimum size requirement for treatment of brain lesions but small foci of potential disease (1-4 mm size) detected on high-resolution MRI may not be clinically relevant and do not count towards the maximum number of 4 brain metastases as per the treating radiation oncologist’s discretion and in line with institutional practice\r\n* A maximum number of 5 target lesions outside the brain, excluding the lung primary, is recommended to ensure that enrollment is limited to patients with low-burden disease and that treatments can be delivered within the specified time frame; this is not an absolute requirement as situations may exist when more than 5 metastatic targets are appropriate in the treating radiation oncologist’s clinical judgment, for example when nearby lesions can be included in a single treatment fieldXx_NEWLINE_xXSymptomatic brain metastases; patients with known brain metastases are eligible if the metastases are asymptomatic and previously treatedXx_NEWLINE_xXPatients with any evidence of distant metastasesXx_NEWLINE_xXMust not have known brain metastasesXx_NEWLINE_xXPatients 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 therapyXx_NEWLINE_xXSubjects with brain metastasis are excluded from this study, and all patients should have brain imaging (either magnetic resonance imaging [MRI] brain or CT brain with contrast) prior to enrollmentXx_NEWLINE_xXSymptomatic brain metastases or brain metastases requiring chronic steroids to control symptoms.Xx_NEWLINE_xXBrain 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 drugXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients 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 yearXx_NEWLINE_xXDistant metastasesXx_NEWLINE_xXSymptomatic brain metastases; patients with known brain metastases are allowed if they are asymptomaticXx_NEWLINE_xXPatients must not have received previous irradiation to the brainXx_NEWLINE_xXEvidence of distant metastasesXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXEvidence of distant metastasesXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXSubjects with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXNo evidence of distant metastasesXx_NEWLINE_xXPreviously 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 enrollmentXx_NEWLINE_xXPatients with untreated brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients with locally treated, stable, and/or asymptomatic brain metastases are eligibleXx_NEWLINE_xXPatients may be enrolled with a history of treated brain metastases that are clinically stable for >= 4 weeks prior to start of study treatmentXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients with brain metastases for whom complete surgical resection is clinically appropriateXx_NEWLINE_xXPatients 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 drugXx_NEWLINE_xXThe 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)Xx_NEWLINE_xXPatients 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 presentXx_NEWLINE_xXPatients with known brain metastases (treated or not) will be excludedXx_NEWLINE_xXPresence of brain metastasesXx_NEWLINE_xXPatients have known active brain metastasisXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatient with a known history or evidence of brain metastasesXx_NEWLINE_xXPatients with symptomatic brain involvementXx_NEWLINE_xXSymptomatic brain metastases (baseline CT scan is not required in asymptomatic patients)Xx_NEWLINE_xXEvidence of distant metastasesXx_NEWLINE_xXPatients with known brain metastases are eligible only if he/she has been treated for brain metastasis, are asymptomatic after treatment, have a stable CT or MRI of the brain within 28 days of enrollment and are not receiving corticosteroid therapy to control symptoms from brain metastasis. Only a non-enzyme inducing anticonvulsant (e.g., Keppra) will be permitted for those patients requiring anticonvulsants. (Topical and/or inhaled steroids are allowed.)Xx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXSubjects 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 requiredXx_NEWLINE_xXMagnetic 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 SRSXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXUntreated, 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 treatmentXx_NEWLINE_xXPatients with documented central nervous system or leptomeningeal metastasis (brain metastasis) at the time of study entry; patients with prior brain metastasis may be considered if they have completed their treatment for brain metastasis, no longer require corticosteroids, and are asymptomaticXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients with known MIBG-avid parenchymal brain metastases are excludedXx_NEWLINE_xXSubjects will be recruited from patients who are potential candidates for SRS treatment at Dartmouth Hitchcock Medical Center (DHMC) for brain metastasesXx_NEWLINE_xXAny patient undergoing SRS for brain metastasesXx_NEWLINE_xXPatients may have had prior therapy including:\r\n* Whole brain radiation therapy (WBRT) > 3 months ago\r\n* SRS to other brain metastasesXx_NEWLINE_xXSubjects with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPrior whole brain irradiationXx_NEWLINE_xXClinically 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 enrollmentXx_NEWLINE_xXKnown brain metastases, unless previously treated and asymptomatic for 3 months and not progressive in size or number for 3 monthsXx_NEWLINE_xXHistory of brain metastases within the last four yearsXx_NEWLINE_xXPatients with cerebral metastasesXx_NEWLINE_xXSymptomatic brain metastasesXx_NEWLINE_xXEvidence of distant metastasesXx_NEWLINE_xXSubjects 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 enrollmentXx_NEWLINE_xXNo more than 1 Brain Met can be treated under this protocolXx_NEWLINE_xXPatients may not have previously been treated with radiosurgery to the brainXx_NEWLINE_xXKnown brain metastasisXx_NEWLINE_xXSubjects with known brain metastases.Xx_NEWLINE_xXSymptomatic brain metastasesXx_NEWLINE_xXPatients with brain metastases for whom complete surgical resection is clinically appropriateXx_NEWLINE_xXKnown 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 DayXx_NEWLINE_xXPatients with prior history of treated brain metastases who are off steroids and have stable metastatic brain disease for at least 3 months are eligibleXx_NEWLINE_xXParticipants with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPrior whole brain irradiationXx_NEWLINE_xXPatient with distant metastasesXx_NEWLINE_xXPatients with rapidly advancing parenchymal brain metastases (Cohort D)Xx_NEWLINE_xXPatient 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 corticosteroidsXx_NEWLINE_xXSpinal cord compression or brain metastasesXx_NEWLINE_xXHas 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.Xx_NEWLINE_xXEvidence of symptomatic brain metastases. Patients with treated (surgically excised or irradiated) and stable brain metastases are eligible, assuming the patient has adequately recovered from treatmentXx_NEWLINE_xXPatients with untreated brain metastases, spinal cord compression, or leptomeningeal carcinomatosis are excluded from this clinical trial; patients with brain metastases or spinal cord compression previously treated with radiation and/or surgery are allowed if local treatment was > 30 days ago, most recent MRI demonstrates stability or decrease in size of all lesions, and the patient has no current neurologic symptoms related to the metastases and treatment and no requirement for corticosteroids related to the prior treatmentXx_NEWLINE_xXPatients 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 metastasesXx_NEWLINE_xXSymptomatic 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 trialXx_NEWLINE_xXPreviously 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.Xx_NEWLINE_xXSymptomatic 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 therapyXx_NEWLINE_xXHepatic metastasesXx_NEWLINE_xXPulmonary metastasesXx_NEWLINE_xXActive 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.Xx_NEWLINE_xXRequirement of radiotherapy to treat brain metastases or receipt of any non-study systemic therapy for cancer or any other experimental/investigational treatment.Xx_NEWLINE_xXHave 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.Xx_NEWLINE_xXUncontrolled brain metastases or treatment by neurosurgical resection or brain biopsy within 4 weeks prior to Day 1.Xx_NEWLINE_xXBrain 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 therapyXx_NEWLINE_xXGreater than 3 presumed melanoma brain metastases on contrast-enhanced brain MRI scan obtained no greater than 4 weeks prior to study registrationXx_NEWLINE_xXNo active central nervous system (CNS) metastases; subjects with neurological symptoms must undergo a head computed tomography (CT) scan or brain magnetic resonance imaging (MRI) to exclude brain metastasis within 28 days of registration; note: a subject with prior brain metastasis may be considered if they have completed their treatment for brain metastasis, no longer require corticosteroids, and are asymptomaticXx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXPatients with brain metastases (except as allowed in section 4.1.14 of the protocol. Neurological assessment will be used to determine brain metastases.Xx_NEWLINE_xXPatient with active brain metastases are not eligible. Patients with treated brain metastases are eligible if :Xx_NEWLINE_xXpresence of 3 brain lesions or lessXx_NEWLINE_xXKnown brain metastases (unless previously treated and well controlled for a period of > or = 3 months).Xx_NEWLINE_xXPresence 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 randomizationXx_NEWLINE_xXPatients with known brain metastases may be included in the study, providing they are clinically stable.Xx_NEWLINE_xXNo evidence of distant metastasesXx_NEWLINE_xXSymptomatic metastatic brain or meningeal tumorsXx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXKnown symptomatic brain metastases requiring steroids.Xx_NEWLINE_xXClinically 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.Xx_NEWLINE_xXKnown history of metastatic brain or meningeal tumors.Xx_NEWLINE_xXKnown 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 enrolmentXx_NEWLINE_xXEither no brain metastases or irradiated stable brain metastasesXx_NEWLINE_xXKnown 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.Xx_NEWLINE_xXHave a history of brain metastasisXx_NEWLINE_xXPatients 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 as long as 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 daysXx_NEWLINE_xXActive or untreated brain metastases or spinal cord compressionXx_NEWLINE_xXKnown 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 eventsXx_NEWLINE_xXBrain 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 metastasisXx_NEWLINE_xXPatients 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)Xx_NEWLINE_xXSymptomatic 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 treatedXx_NEWLINE_xXPatients 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 participateXx_NEWLINE_xXPatients 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 participateXx_NEWLINE_xXPrior whole brain irradiationXx_NEWLINE_xXKnown 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.Xx_NEWLINE_xXSymptomatic 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 stabilityXx_NEWLINE_xXPatients with any evidence of distant metastasesXx_NEWLINE_xXPatients with previously untreated and or symptomatic brain metastases are excluded from this clinical trialXx_NEWLINE_xXHas 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 treatmentXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXIn 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 compressionXx_NEWLINE_xXDocumented primary brain malignancy or brain metastasesXx_NEWLINE_xXPrior whole brain irradiation.Xx_NEWLINE_xXPatients 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 as long as 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.Xx_NEWLINE_xXSymptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroidsXx_NEWLINE_xXPatients 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 eventsXx_NEWLINE_xXKnown untreated brain metastasis or brain metastasis treated within 3 months prior to enrollment in this trialXx_NEWLINE_xXPatients with brain metastasisXx_NEWLINE_xXPatients 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 randomizationXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients 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 registrationXx_NEWLINE_xXPatients 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 registrationXx_NEWLINE_xXKnown brain metastases (even if treated)Xx_NEWLINE_xXSubjects with known symptomatic brain metastasis are not suitable for enrolment. Subjects with asymptomatic, stable, treated brain metastases are eligible for study entry.Xx_NEWLINE_xXParticipants with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXKnown brain metastases or CNS cancer unless adequately treated with radiotherapy and/or surgery and stable for ? 2 moXx_NEWLINE_xXPatients with active brain metastases or leptomeningeal metastasesXx_NEWLINE_xXActive brain metastasesXx_NEWLINE_xXPatients with known active or history of brain metastases should be excluded from this clinical trialXx_NEWLINE_xXParticipants with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXSymptomatic brain or spinal cord metastases (patients must be stable for > 1 month post radiotherapy or surgery).Xx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients 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 ineligibleXx_NEWLINE_xXDistant metastasesXx_NEWLINE_xXParticipants 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)Xx_NEWLINE_xXSymptomatic or untreated brain metastasisXx_NEWLINE_xXActive central nervous system (CNS) metastases; subjects with neurological symptoms should undergo a head computed tomography (CT) scan or brain magnetic resonance imaging (MRI) to exclude brain metastasis, at the discretion of the treating physician\r\n* NOTE: A subject with prior brain metastasis may be considered if they have completed their treatment for brain metastasis, no longer require corticosteroids, and are asymptomaticXx_NEWLINE_xXPatients with known brain metastasesXx_NEWLINE_xXPatients 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 treatmentXx_NEWLINE_xXDOSE ESCALATION COHORT: Brain metastases: symptomatic, unstable, or disease requiring use of steroid treatmentXx_NEWLINE_xXDOSE EXPANSION COHORT: Brain metastases: symptomatic, unstable, or disease requiring use of steroid treatmentXx_NEWLINE_xXPatients 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 trialXx_NEWLINE_xXPatients 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)Xx_NEWLINE_xXPatients with brain metastasesXx_NEWLINE_xXSubjects 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 drugXx_NEWLINE_xXA 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, and are asymptomatic.Xx_NEWLINE_xXPatients 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 metastasesXx_NEWLINE_xXSymptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroidsXx_NEWLINE_xXPatients with cerebral metastasesXx_NEWLINE_xXUntreated brain metastasesXx_NEWLINE_xXParticipants with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXSubjects 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 enrolledXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXSymptomatic brain metastasisXx_NEWLINE_xXPatients with known brain metastases are excludedXx_NEWLINE_xXPatients 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 dailyXx_NEWLINE_xXPatients 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 drugXx_NEWLINE_xXActive 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 administrationXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients 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 treatmentXx_NEWLINE_xXLeptomeningeal or brain metastases 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 2 weeks can be enrolled with approval of the Cancer Therapy Evaluation Program (CTEP) medical monitor; subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeksXx_NEWLINE_xXKnown brain metastases, except brain metastases that have been previously removed or irradiated and currently have no clinical impactXx_NEWLINE_xXIf 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 metastasesXx_NEWLINE_xXBrain 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 eligibleXx_NEWLINE_xXResection of brain metastases, otherwise untreated with radiation for those brain lesions (presenting for postoperative consolidative radiotherapy)Xx_NEWLINE_xXOne brain metastasis or brain metastasis resection cavity with maximal diameter >= 3 cm (or >= 14 cc) and =< 6 cm (or =< 113 cc)Xx_NEWLINE_xXActive 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 trialXx_NEWLINE_xXThe subject has untreated, symptomatic or uncontrolled brain metastasis requiring current treatment including steroids and anti-convulsants; neurosurgical resection of brain metastasis or brain biopsy is permitted if completed at least 3 months before the first dose of study treatmentXx_NEWLINE_xXPatients 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 investigatorXx_NEWLINE_xXSubjects with brain metastasisXx_NEWLINE_xXExtensive 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 eligibleXx_NEWLINE_xXSubjects with known brain metastasesXx_NEWLINE_xXPatients with stable and controlled brain metastases for at least 3 months who also do not require steroidsXx_NEWLINE_xXPrimary brain tumors or active brain metastasesXx_NEWLINE_xXPatients with brain metastases (including treated or stable brain metastases)Xx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients must not have active brain metastases from a systemic solid tumorXx_NEWLINE_xXSymptomatic metastatic brain or meningeal tumorsXx_NEWLINE_xXPatients with known brain metastases should be excluded from early clinical trialsXx_NEWLINE_xXSubjects 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 listedXx_NEWLINE_xXUntreated brain metastasisXx_NEWLINE_xXPatients with untreated brain or meningeal metastasesXx_NEWLINE_xXHistory of symptomatic metastatic brain or meningeal tumors unless the subject is > 3 months from definitive therapy and has no evidence of tumor growth on an imaging study within 2 weeks prior to study entry; subjects with brain metastases must not be undergoing acute corticosteroid therapy or steroid taper; chronic steroid therapy is acceptable provided that the dose is stable for one month prior to screeningXx_NEWLINE_xXBrain 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 WBRTXx_NEWLINE_xXHistory 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 malformationsXx_NEWLINE_xXPatients with treated brain metastasis as long as neurologically stable and not on steroids for at least 12 weeksXx_NEWLINE_xXPatients with known brain metastasisXx_NEWLINE_xXSubjects with previously treated brain metastases who are free of central nervous system (CNS) symptoms and are > 3 months from treatment of brain metastases are eligibleXx_NEWLINE_xXPatients 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 administrationXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients 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 includedXx_NEWLINE_xXPatients 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 ccXx_NEWLINE_xXPatients who have previously been treated with whole brain radiationXx_NEWLINE_xXPatients with treated, stable, and asymptomatic brain metastases are eligibleXx_NEWLINE_xXUntreated, progressing, or symptomatic brain metastasesXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXExtensive active brain disease including symptomatic brain metastases or presence of leptomeningeal diseaseXx_NEWLINE_xXHistory of another malignancy that makes determination of the source of the brain metastases uncertainXx_NEWLINE_xXPatients with documented central nervous system or leptomeningeal metastasis (brain metastasis) at the time of study entry; patients with prior brain metastasis may be considered if they have completed their treatment for brain metastasis and no longer require corticosteroidsXx_NEWLINE_xXPatients 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 investigatorXx_NEWLINE_xXExtensive 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 eligibleXx_NEWLINE_xXBrain metastases that are symptomatic or requiring corticosteroids (except inhaled); subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeksXx_NEWLINE_xXStudy 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 daysXx_NEWLINE_xXDistant metastasesXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXUntreated brain metastases (or local treatment of brain metastases within the last 6 months)Xx_NEWLINE_xXNo 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 eligibilityXx_NEWLINE_xXBrain metastases or a history of brain metastasesXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients 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 metastasesXx_NEWLINE_xXAt 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 therapyXx_NEWLINE_xXPretreatment brain CT with contrast or brain magnetic resonance imaging (MRI) to rule out metastasesXx_NEWLINE_xXPatients must be free of brain metastasis by contrast-enhanced computed tomography (CT)/magnetic resonance imaging (MRI) scans within 4 weeks prior to enrollment; if known to have prior brain metastases, must not have evidence of active brain disease after definitive therapy (surgery, radiation therapy or stereotactic radiosurgery) on two successive MRI evaluations at least 3 months apart (one of which is =< 4 weeks prior to starting the study drugs)Xx_NEWLINE_xXPrior 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 enrollmentXx_NEWLINE_xXSymptomatic 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 enrollmentXx_NEWLINE_xXPatients with known brain metastasesXx_NEWLINE_xXSubjects 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-treatmentXx_NEWLINE_xXPatients with symptomatic brain metastases are excluded from this studyXx_NEWLINE_xXVisceral metastases (e.g. lung, liver, brain, kidney, spleen)Xx_NEWLINE_xXSubjects with known brain metastasesXx_NEWLINE_xXPatients with known distant metastasesXx_NEWLINE_xXPatients with known brain metastasesXx_NEWLINE_xXPatients 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)Xx_NEWLINE_xXPatients 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 enrollmentXx_NEWLINE_xXPatients with brain metastasis have no signs of progressive disease 4 months after the completion of brain metastasis treatment (radiation therapy, surgery, etc.) do not require anticonvulsants or corticosteroids, and have been off such drugs for at least 7 daysXx_NEWLINE_xXPatients 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 steroidsXx_NEWLINE_xXPatients with known brain metastases with active symptoms or requiring anticonvulsive medications, or steroids should be excluded from this clinical trialXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXKnown brain metastasisXx_NEWLINE_xXPrior 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 steroidsXx_NEWLINE_xXPatients 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 monthsXx_NEWLINE_xXSubjects 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 treatmentXx_NEWLINE_xXParticipants with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients 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 symptomsXx_NEWLINE_xXHistologically confirmed malignant melanoma with measurable metastases in the brain. Both asymptomatic and symptomatic patients.Xx_NEWLINE_xXPatients 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 diseaseXx_NEWLINE_xXSymptomatic or uncontrolled brain metastases;Xx_NEWLINE_xXNSCLC subjects with known brain metastases (certain exceptions allowed)Xx_NEWLINE_xXGastric adenocarcinoma subjects with brain metastasesXx_NEWLINE_xXActive brain metastases or leptomeningeal metastases are not allowed.Xx_NEWLINE_xXEvidence 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).Xx_NEWLINE_xXPatients with known symptomatic brain metastases requiring steroids.Xx_NEWLINE_xXUntreated 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).Xx_NEWLINE_xXException: 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.Xx_NEWLINE_xXEvidence of distant metastasesXx_NEWLINE_xXPatients 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 PIXx_NEWLINE_xXAll 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)Xx_NEWLINE_xXProgression of or new brain metastases after completion of whole-brain radiotherapy or stereotactic radiosurgeryXx_NEWLINE_xXPatients with brain metastases that are untreated, symptomatic, or require therapy to control symptoms; or any radiation, surgery, or other therapy, including those used to control symptoms, within 1 month of first doseXx_NEWLINE_xXActive brain metastases or leptomeningeal metastasesXx_NEWLINE_xXKnown brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery and stable for at least 3 months before randomization.Xx_NEWLINE_xXDISEASE RELATED CRITERIA: Patients must not have known brain metastases, leptomeningeal carcinomatosis or spinal cord compression unless: (1) metastases have been locally treated (including stereotactic body radiation therapy [SBRT], whole brain radiotherapy [WBRT], and surgical resection) and have remained clinically controlled and asymptomatic for at least 14 days following treatment and prior to registration, AND (2) patient has no residual neurological dysfunction and has been off corticosteroids for at least 24 hours prior to registrationXx_NEWLINE_xXKnown 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.Xx_NEWLINE_xXBrain metastases considered unstable as:Xx_NEWLINE_xXSubject has symptomatic brain metastases, spinal cord compression, or intractable back pain due to compression of destructive mass.Xx_NEWLINE_xXExtensive active brain disease including symptomatic brain metastases or the presence of leptomeningeal disease, and all patients with infratentorial tumors\r\n* Note: patients with brain metastasis after definitive therapy with surgery or stereotactic radiation and stable off steroids for > 4 weeks are eligible as are patients with asymptomatic brain metastasis as long as less than 1 cm and thus deemed as not requiring therapy by the primary physician and the lesions(s) are not infratentorialXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXKnown brain metastases, unless stable or previously treated.Xx_NEWLINE_xXPatients 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 imagingXx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXPresence of or known history of brain/CNS tumor or metastasesXx_NEWLINE_xXKnown 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 physicianXx_NEWLINE_xXKnown 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 randomizationXx_NEWLINE_xXParticipants 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.Xx_NEWLINE_xXHistory of brain metastases that meet certain conditions;Xx_NEWLINE_xXBrain metastases considered unstable as:Xx_NEWLINE_xXPatients 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 steroidsXx_NEWLINE_xXHave known brain metastases.Xx_NEWLINE_xXUntreated or symptomatic brain metastasesXx_NEWLINE_xXSymptomatic or progressive brain metastases.Xx_NEWLINE_xXPatients must not have history of brain metastasesXx_NEWLINE_xXAt 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 consultantXx_NEWLINE_xXNon-malignant neurological disease that would interfere with evaluation of symptoms or signs of brain metastasesXx_NEWLINE_xXUntreated brain metastasesXx_NEWLINE_xXUntreated or symptomatic brain metastasesXx_NEWLINE_xXNo known brain metastasesXx_NEWLINE_xXSubjects 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.Xx_NEWLINE_xXPatients with symptomatic brain metastases are excluded from this clinical trialXx_NEWLINE_xXSymptomatic or untreated leptomeningeal or brain metastases or spinal cord compression. NOTE: Subjects previously treated for these conditions that have had stable central nervous system disease (verified with consecutive imaging studies) for >1 month, are asymptomatic and off corticosteroids, or are on stable dose of corticosteroids for at least 1 month prior to study Day 1 are permitted. Stability of brain metastases must be confirmed with imaging. Subject treated with gamma knife the can be enrolled 2 weeks post-procedure as long as there are no post-procedure complications/stable. In addition, subjects treated or currently taking enzyme-inducing anticonvulsant are allowed on study.Xx_NEWLINE_xXPatients 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 enrollmentXx_NEWLINE_xXActive brain metastases or leptomeningeal metastasesXx_NEWLINE_xXBrain metastases, unless previously treated and asymptomatic and not progressive for 2 months.Xx_NEWLINE_xXSymptomatic brain or meningeal tumors.Xx_NEWLINE_xXKnown 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).Xx_NEWLINE_xXSubject 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.Xx_NEWLINE_xXPresence of symptomatic brain metastases requiring immediate treatment with radiation therapy or steroids.Xx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXHave known brain metastases.Xx_NEWLINE_xXAny 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 treatedXx_NEWLINE_xXPresence of brain metastasesXx_NEWLINE_xXCancer metastases in the brainXx_NEWLINE_xXSubjects 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 diseaseXx_NEWLINE_xXAny brain metastases including leptomeningeal metastases, are excluded, even if treated and stable.Xx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXSubject 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)Xx_NEWLINE_xXSymptomatic metastatic brain or meningeal tumorsXx_NEWLINE_xXPatients with known brain metastasesXx_NEWLINE_xXHistory of brain or other CNS metastases.Xx_NEWLINE_xXPatients with uncontrolled brain metastases; patients with brain metastasis must be asymptomatic and off corticosteroid use for at least one weekXx_NEWLINE_xXUncontrolled or symptomatic brain metastasisXx_NEWLINE_xXPatients 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 administrationXx_NEWLINE_xXNew or progressive brain or meningeal or spinal metastasesXx_NEWLINE_xXSpinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 6 weeks prior to start of study treatmentXx_NEWLINE_xXSubjects with active brain metastases or leptomeningeal metastasesXx_NEWLINE_xXParticipants 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.Xx_NEWLINE_xXKnown 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 equivalentXx_NEWLINE_xXPatients with untreated brain metastasesXx_NEWLINE_xXHistory of or active CNS metastasis (brain, leptomeningeal or cord compression). Brain imaging studies are not required for eligibility if the subject has no neurologic signs or symptoms suggestive of brain metastasis. Subjects with neurological symptoms are recommended to undergo a head CT scan (with or without intravenous contrast) or brain MRI (with or without intravenous contrast) to exclude brain metastasis. If brain imaging studies are performed, they must be negative for CNS disease. Skull bone involvement without neurological impact by prostate cancer is allowed.Xx_NEWLINE_xXPatients with any metastasis in the brain or meninx that is symptomatic or requires treatmentXx_NEWLINE_xXDocumented or symptomatic brain metastases and/or central nervous system metastases or leptomeningeal diseaseXx_NEWLINE_xXAny 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.Xx_NEWLINE_xXPresence of brain or subdural metastasesXx_NEWLINE_xXAny signs and/or symptoms of brain metastases must be stable for ? 4 weeksXx_NEWLINE_xXSubjects with previously treated brain metastasis (es) that is asymptomatic or radiographically/clinically stable and not requiring steroids medications for 4 weeks prior to enrollment are permitted.Xx_NEWLINE_xXSymptomatic 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)Xx_NEWLINE_xXPrimary brain malignant tumorsXx_NEWLINE_xXKnown metastases to the brainXx_NEWLINE_xXMagnetic resonance imaging (MRI) or CT scans of brain if there are symptoms or signs suggesting brain metastases, must be done within 10 weeks prior to study entryXx_NEWLINE_xXPatients with symptomatic brain metastases.Xx_NEWLINE_xXDocumented brain metastasesXx_NEWLINE_xXSubject has known brain metastasesXx_NEWLINE_xXNo symptomatic, untreated, or uncontrolled brain metastases presentXx_NEWLINE_xXKnown or suspected brain metastasisXx_NEWLINE_xXPatients with known brain metastases are excluded from this clinical trial; patients with primary brain tumors amenable to surgery are allowed on this protocolXx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXINCLUSION 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.Xx_NEWLINE_xXActive brain metastases: evidence of progression =< 3 months after local therapy (patients should be asymptomatic and off corticosteroids and anticonvulsants for at least 3 months prior to study entry)Xx_NEWLINE_xXActive 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 drugXx_NEWLINE_xXPresence of distant metastasesXx_NEWLINE_xXKnown 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 metastasesXx_NEWLINE_xXPresence of central nervous system metastasis (including active brain metastasis); active brain metastasis would be defined as untreated brain metastases; if the brain metastases have received prior treatment (usually either with surgery or radiation), they are no longer activeXx_NEWLINE_xXKnown untreated brain metastasesXx_NEWLINE_xXActive brain metastases (e.g. stable for < 4 weeks)Xx_NEWLINE_xXSymptomatic uncontrolled brain metastasesXx_NEWLINE_xXPatients 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 eventsXx_NEWLINE_xXPatients with known metastases are not eligibleXx_NEWLINE_xXPatient has evidence of distant metastasesXx_NEWLINE_xXAny history of or current brain or subdural metastasesXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXThe 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)Xx_NEWLINE_xXPatients with untreated brain metastases should be excluded from this clinical trialXx_NEWLINE_xXBrain metastases unless resected or irradiated and stable >= 4 weeksXx_NEWLINE_xXPatients must not have known brain metastases because the study drug has not been adequately tested in this settingXx_NEWLINE_xXClinically 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 enrollmentXx_NEWLINE_xXHave 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.Xx_NEWLINE_xXActive 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 eligibleXx_NEWLINE_xXSubjects who have brain metastasis as the only measureable lesionXx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXPatient 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 studyXx_NEWLINE_xXPatients with brain metastasisXx_NEWLINE_xXPatients have known active brain metastasisXx_NEWLINE_xXPresence of symptomatic brain metastases requiring immediate treatment with radiation therapy or steroids.Xx_NEWLINE_xXBrain 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).Xx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXSubjects with treated brain metastases must have been treated with surgery and/or radiation therapy ? 21 days pre-study and must be clinically stable.Xx_NEWLINE_xXPatients 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 administrationXx_NEWLINE_xXPatients with spinal cord compression, carcinomatous meningitis, or leptomeningeal disease are excluded; patients with a history of prior brain metastasis are permitted provided the lesions are fully treated, inactive, and patient is asymptomatic; subjects with new evidence of brain metastasis discovered during screening are allowed as long as the brain lesions have been irradiated; lesions must be stable as evidenced by repeat magnetic resonance imaging (MRI) brain imaging within 2 weeks prior to starting study treatment; patients must also be asymptomatic; patient must have had no steroids use for at least 28 days prior to start of treatment; centrally located tumors with radiographic evidence (computed tomography [CT] or MRI) of local invasion of major blood vesselsXx_NEWLINE_xXParticipants with symptomatic or growing brain metastases less than 4 weeks prior to enrollment.Xx_NEWLINE_xXSymptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroidsXx_NEWLINE_xXPatients 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 purposeXx_NEWLINE_xXSubjects who have new or progressive brain or meningeal or spinal metastases.Xx_NEWLINE_xXUntreated 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 drugXx_NEWLINE_xXBrain metastases, meningeal tumours or other metastases in the central nervous systemXx_NEWLINE_xXBrain metastases or spinal cord compression.Xx_NEWLINE_xXPatients with primary brain tumors are excluded; patients with metastatic brain tumors may be enrolledXx_NEWLINE_xXHas known brain metastasesXx_NEWLINE_xXPatients with uncontrolled symptomatic brain metastases; a scan to confirm absence of brain metastasis is not requiredXx_NEWLINE_xXThe 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)Xx_NEWLINE_xXPresence of symptomatic brain metastases requiring immediate treatment with radiation therapy or steroids.Xx_NEWLINE_xXKnown spinal cord compression or brain or liver metastasisXx_NEWLINE_xXUnstable brain metastases or spinal cord compressionXx_NEWLINE_xXSymptomatic metastatic brain or meningeal tumorsXx_NEWLINE_xXThe participant has brain metastases that are symptomatic.Xx_NEWLINE_xXUntreated or progressive brain metastases; patients with treated brain metastases not requiring chronic corticosteroids for symptom control are eligibleXx_NEWLINE_xXParticipants with known uncontrolled brain metastases will be excluded from this clinicalXx_NEWLINE_xXThere is no limit on the number of brain metastasesXx_NEWLINE_xXThe 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)Xx_NEWLINE_xXPatients with known brain metastases or spinal cord compression should be excluded from this clinical trialXx_NEWLINE_xXKnown 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 excludedXx_NEWLINE_xXSymptomatic 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 allowedXx_NEWLINE_xXParticipants with known brain metastasesXx_NEWLINE_xXSubject has a history of, or current symptomatic brain metastasis.Xx_NEWLINE_xXSymptomatic central nervous system metastases; subjects with brain metastases that have been previously treated and are stable for 4 weeks are allowedXx_NEWLINE_xXBrain metastases or spinal cord compression unless asymptomatic, treated and stable (not requiring steroids)Xx_NEWLINE_xXSymptomatic brain metastases; known brain metastases are allowed if asymptomatic and previously treatedXx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXPatients 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 drugXx_NEWLINE_xXActive 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 imagingXx_NEWLINE_xXKnown 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 excludedXx_NEWLINE_xXPatient has uncontrolled or severe intercurrent medical condition (including uncontrolled brain metastases). Patients with stable brain metastases either treated or being treated with a stable dose of steroids/anticonvulsants are allowed provided there is no dose change within 4 weeks before the first dose of PBI 05204, and no anticipated dose change during study participation.Xx_NEWLINE_xXPatients 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 protocolXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXSpinal cord compression, symptomatic and unstable brain metastases, except for those patients who have completed definitive therapy, are not on steroids, have a stable neurologic status for at least 2 weeks after completion of the definitive therapy and steroids.Xx_NEWLINE_xXKnown brain metastasisXx_NEWLINE_xXDistant metastatic disease, including known brain metastasesXx_NEWLINE_xXUncontrolled 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)Xx_NEWLINE_xXSymptomatic or untreated leptomeningeal or brain metastases or spinal cord compression; treated brain metastases must have been stable for at least 1 monthXx_NEWLINE_xXUntreated or progressive brain metastasesXx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXPatients with “treated and stable” brain lesions of a duration of >= 2 months may be enrolledXx_NEWLINE_xXPatient has a known history or evidence of brain metastasesXx_NEWLINE_xXOne or more brain metastasesXx_NEWLINE_xXPrior radiation therapy to the brain is allowed with the exception of whole brain irradiationXx_NEWLINE_xXPatients who have symptomatic, uncontrolled spinal cord compression and/or brain metastases; a scan to confirm absence of brain metastasis is not required; patients can receive a stable dose of corticosteroids (except those prohibited per protocol) before/during study if these were started at least 28 days prior to entryXx_NEWLINE_xXParticipants with known brain metastases will be excluded from this clinical trialXx_NEWLINE_xXThe presence of known brain metastases, malignant pleural effusions, or malignant ascites; brain MRI is required at screening only if clinically indicatedXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXBrain metastases per magnetic resonance imaging (MRI) or computed tomography (CT)\r\n* Note: patients who have had therapy for brain metastasis (i.e., surgical resection, whole brain radiation, or stereotactic radiosurgery [SRS] even if stable) are not eligibleXx_NEWLINE_xXIf the patient has brain metastasis, they must have been stable (treated and/or asymptomatic) and the patient must have been off steroids for at least 2 weeksXx_NEWLINE_xXPatients 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 entryXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXParticipants with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPreviously untreated brain metastases.Xx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXSymptomatic metastatic brain or meningeal tumorsXx_NEWLINE_xXPatients with known brain metastasesXx_NEWLINE_xXHistory of, or current metastases in the brain, meninges, or untreated spinal cord compressionXx_NEWLINE_xXActive brain metastases or leptomeningeal metastases are not allowedXx_NEWLINE_xXSymptomatic metastatic brain or meningeal tumors (asymptomatic or treated metastatic brain and leptomeningeal tumors are allowed)Xx_NEWLINE_xXSubjects 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;Xx_NEWLINE_xXSymptoms or signs of active brain metastases;Xx_NEWLINE_xXPatients with untreated or progressing brain metastasesXx_NEWLINE_xXHistory of, or current known metastases in the brain or untreated spinal cord compressionXx_NEWLINE_xXBrain metastases or spinal cord compression or unless asymptomatic, treated and stable (not requiring steroids).Xx_NEWLINE_xXKnown brain metastases;Xx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients 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 metastasesXx_NEWLINE_xXPatients 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 treatmentXx_NEWLINE_xXPatients with either untreated brain metastases or brain metastases treated within the past three months are ineligibleXx_NEWLINE_xXHistory of or known brain metastasis.Xx_NEWLINE_xXPHASE I: Participants with untreated or uncontrolled brain metastases are excluded from this clinical trial; patients with treated and stable (> 4 weeks) brain metastasis are allowedXx_NEWLINE_xXPHASE II: Participants with known brain metastases should be excludedXx_NEWLINE_xXThe 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)Xx_NEWLINE_xXSymptomatic brain or spinal cord metastases (patients must be stable for > 3 months post radiotherapy or surgery) for subjects with mesothelioma, NSCLC, uveal melanoma excludes subjects with HCC or glioma).Xx_NEWLINE_xXKnown brain metastasisXx_NEWLINE_xXAny 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.Xx_NEWLINE_xXParticipants 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 imagingXx_NEWLINE_xXHave active cancer in the brain or spinal cordXx_NEWLINE_xXUntreated and/or uncontrolled brain metastases.Xx_NEWLINE_xXAt the time of day 1 of the study, subjects with brain metastases must be asymptomatic for at least 4 weeks and:Xx_NEWLINE_xXat least 3 weeks without new brain metastases as evidenced by MRI/CTXx_NEWLINE_xXSpinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatment.Xx_NEWLINE_xXUntreated brain metastases (or local treatment of brain metastases within the last 6 months)Xx_NEWLINE_xXParticipants with known brain metastasesXx_NEWLINE_xXIndividuals 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 enrollmentXx_NEWLINE_xXThe patient has a primary brain tumor(s) or brain metastasis (unless metastasis is treated and stable for > 28 days). In patients who are symptomatic, a brain scan is required to exclude metastasis.Xx_NEWLINE_xXKnown brain metastasisXx_NEWLINE_xXSymptomatic brain metastases or brain metastases requiring chronic steroids to control symptoms.Xx_NEWLINE_xXParticipants with metastases are excluded if their brain metastases are:\r\n* Symptomatic\r\n* Treated (e.g., surgery, radiation therapy) but not clinically and radiographically stable one month after therapy (as assessed by at least two distinct contrast enhanced MRI or CT scans over at least a one month period), OR\r\n* Asymptomatic and untreated but > 1 cm in the longest dimensionXx_NEWLINE_xXSymptomatic 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 treatmentXx_NEWLINE_xXBrain metastases requiring steroidsXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients 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 investigatorXx_NEWLINE_xXUntreated brain metastases.Xx_NEWLINE_xXAbsence 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.Xx_NEWLINE_xXPatients with “treated and stable” brain lesions of a duration of >= 2 months may be enrolledXx_NEWLINE_xXPatients with known brain metastases requiring steroids.Xx_NEWLINE_xXParticipants with symptomatic or progressive brain metastases, or requiring steroids to control symptoms of brain metastasesXx_NEWLINE_xXNo known or suspected brain metastases (NOTE: patients with treated epidural disease are allowed)Xx_NEWLINE_xXKnown 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 edemaXx_NEWLINE_xXKnown brain metastasisXx_NEWLINE_xXSymptomatic or uncontrolled brain metastasis; patients with neurological symptoms must undergo a computed tomography (CT) scan/magnetic resonance imaging (MRI) of the brain to exclude brain metastasis; previously treated brain metastases will be allowed as long as the patient is neurologically stable and is off steroids and anticonvulsantsXx_NEWLINE_xXSymptomatic or uncontrolled brain metastasis; patients with neurological symptoms must undergo a computed tomography (CT) scan/magnetic resonance imaging (MRI) of the brain to exclude brain metastasis; previously treated brain metastases will be allowed as long as the patient is neurologically stable and is off steroids and anticonvulsants at the time of registrationXx_NEWLINE_xXActive 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 surgeryXx_NEWLINE_xXAll 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 eligibleXx_NEWLINE_xXDiagnosis 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 AEsXx_NEWLINE_xXPatients must have radiographically-confirmed recurrent brain metastases from a solid tumor after WBRTXx_NEWLINE_xXPatients with treated brain metastases that have been stable for 1 month are eligible; patients must be off steroids for week prior to starting study treatmentXx_NEWLINE_xXParticipants with known brain metastasesXx_NEWLINE_xXUncontrolled brain or spinal cord metastasesXx_NEWLINE_xXSubjects 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.Xx_NEWLINE_xXLeptomeningeal metastases or brain metastases except as for Inclusion Criterion #6.Xx_NEWLINE_xXPatients will be excluded if they have had prior surgical resection of brain for other brain tumorsXx_NEWLINE_xXParticipants 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 participationXx_NEWLINE_xXPatients with known brain metastases will be excluded from this clinical trialXx_NEWLINE_xXUncontrolled 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.Xx_NEWLINE_xXActive brain metastases or leptomeningeal metastasesXx_NEWLINE_xXBrain metastases are allowed if well controlled and without seizuresXx_NEWLINE_xXNo distant metastasesXx_NEWLINE_xXActive metastases.Xx_NEWLINE_xXKnown brain metastases, unless stable for at least 28 daysXx_NEWLINE_xXKnown symptomatic or uncontrolled brain metastases or epidural diseaseXx_NEWLINE_xXKnown untreated, symptomatic, or progressive brain metastases; presence of carcinomatous meningitis; history of intracranial hemorrhage; or brain metastases requiring chronic steroidsXx_NEWLINE_xXPatients 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 contraindicatedXx_NEWLINE_xXActive 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 trialXx_NEWLINE_xXPatients 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 entryXx_NEWLINE_xXParticipants with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXParticipants with known brain metastasesXx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXAny known metastasesXx_NEWLINE_xXAny 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.Xx_NEWLINE_xXKnown uncontrolled brain metastases. Stable brain metastases either treated or being treated with a stable dose of steroids/anticonvulsantsXx_NEWLINE_xXAny 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.Xx_NEWLINE_xXHistory or evidence of brain metastasesXx_NEWLINE_xXKnown brain metastasisXx_NEWLINE_xXPatients with known brain metastases are NOT eligible for participationXx_NEWLINE_xXBrain 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 requiredXx_NEWLINE_xXSymptomatic brain metastasisXx_NEWLINE_xXPatients 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 eventsXx_NEWLINE_xXPatients with known brain metastasesXx_NEWLINE_xXPatients 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 participationXx_NEWLINE_xXThe 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 eligibilityXx_NEWLINE_xXPatient must not have known brain metastases; patients with known brain metastases must be excluded from this clinical trialXx_NEWLINE_xXDocumented and ongoing brain metastasesXx_NEWLINE_xXHistologically or radiologically confirmed diagnosis of brain cancer:\r\n* Glioblastoma (GBM), \r\n* Anaplastic astrocytoma (AA), \r\n* Anaplastic oligodendroglioma (AO), \r\n* Anaplastic mixed oligoastrocytoma (AMO), \r\n* Low grade gliomas, \r\n* Brain metastases, \r\n* Meningiomas, or\r\n* Leptomeningeal metastasesXx_NEWLINE_xXParticipants with known brain metastases should be excluded from this clinical trial; does not apply to group CXx_NEWLINE_xXParticipants may have brain metastasisXx_NEWLINE_xXPatient with central nervous system (CNS) metastasis are required to have stable disease documented by being off treatment (surgery, radiation therapy) for at least 2 weeks, and four (4) weeks is preferred; a contrast enhanced brain computed tomography (CT) or brain magnetic resonance imaging (MRI) is required within 35 days of enrollment; patients with brain metastases who qualify for protocol therapy will be included in Cohort 2 (ineligible for treatment with bevacizumab)Xx_NEWLINE_xXPatients must not have hemoptysis, squamous histology, brain metastasisXx_NEWLINE_xXDocumented brain metastasesXx_NEWLINE_xXSymptomatic or clinically active brain metastasesXx_NEWLINE_xXSubjects must be free of known brain metastases by contrast-enhanced computed tomography (CT)/magnetic resonance imaging (MRI) scans or have successfully-treated brain metastases and be asymptomatic for more than 1 monthXx_NEWLINE_xXAbsence of brain metastases as confirmed by imaging of the brain by MRI or CT brain with contrast performed at baseline screeningXx_NEWLINE_xXPatients 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 enrolledXx_NEWLINE_xXPatients 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 steroidsXx_NEWLINE_xXConcurrent radiation therapy is not allowed with the exception of brain metastases developing on study treatmentXx_NEWLINE_xXPatients with unresectable lung metastasesXx_NEWLINE_xXThe 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)Xx_NEWLINE_xXPatients with active or untreated brain metastases; treated brain metastases must have been stable for at least 2 monthsXx_NEWLINE_xXKnown 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.Xx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXKnown presence of metastasesXx_NEWLINE_xXUntreated or progressive brain metastases; patients with treated brain metastases not requiring chronic corticosteroids for symptom control are eligibleXx_NEWLINE_xXSubjects 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 eventsXx_NEWLINE_xXKnown 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)Xx_NEWLINE_xXSubjects 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 listedXx_NEWLINE_xXCNS or Brain metastasesXx_NEWLINE_xXPatients with evidence upon physical examination of brain tumor and any brain metastasesXx_NEWLINE_xXSubjects 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 enrollmentXx_NEWLINE_xXKnown 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 excludedXx_NEWLINE_xXPresence of untreated brain metastases; if patients have had previous treatment for brain metastasis, an MRI or CT scan of the brain must confirm the stabilization of the brain metastasis for more than 4 weeksXx_NEWLINE_xXKnown 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 excludedXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXActive brain metastasesXx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXPreviously treated NSCLC with asymptomatic brain metastases (eligible for Arm M) See additional details belowXx_NEWLINE_xXNo more than 4 brain metastasesXx_NEWLINE_xXEach brain metastases ?3 cm in sizeXx_NEWLINE_xXSubjects with symptomatic brain metastases, spinal cord compression, or intractable back pain due to a compressive or destructive massXx_NEWLINE_xXSubjects with known brain metastases and/or unresectable sarcomaXx_NEWLINE_xXSymptomatic brain metastasisXx_NEWLINE_xXPatients with measurable brain metastasis outside a 5-mm margin around either hippocampusXx_NEWLINE_xXUncontrolled brain metastases and infections; patients with brain metastases treated with gamma knife (GK) or whole brain radiation within 24 hours of registrationXx_NEWLINE_xXFour or fewer brain metastases (as defined on the pre-operative MRI or CT brain scan) and status post resection of one of the lesionsXx_NEWLINE_xXAny 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 eligibilityXx_NEWLINE_xXSymptomatic brain metastases (prior treatment and stable metastases are allowed)Xx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXSubjects with brain metastases are excluded if their brain metastases are:Xx_NEWLINE_xXPreviously 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 weeksXx_NEWLINE_xXActive seizure disorder or evidence of brain metastases; (appropriate imaging should be done to rule out brain metastases)Xx_NEWLINE_xXHistologically confirmed HER2-positive (immunohistochemistry [IHC] 3+ or fluorescence in situ hybridization [FISH] amplified; by clinical assay on either primary or metastatic tumor) adenocarcinoma of the breast with at least one progressive and/or new metastatic brain lesion (>= 5 mm on radiographic imaging); patients in whom brain metastases (BM) are asymptomatic and detected during routine brain magnetic resonance imaging (MRI) screening per institutional protocols are eligibleXx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXUnstable 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)Xx_NEWLINE_xXPatients 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 investigatorXx_NEWLINE_xXKnown or suspected brain metastasesXx_NEWLINE_xXPatients with hemorrhagic brain metastasesXx_NEWLINE_xXPatients 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 registrationXx_NEWLINE_xXHistory 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 excludedXx_NEWLINE_xXEXPANSION 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 excludedXx_NEWLINE_xXPatients with brain metastasesXx_NEWLINE_xXPatients with distant metastasesXx_NEWLINE_xXSubjects 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 daysXx_NEWLINE_xXKnown brain metastases or cranial epidural disease unless adequately treated and stable for at least 4 weeks before first dose of study treatment.Xx_NEWLINE_xXPatients with brain metastases are allowed onto the study as long as patients have completed their treatment for brain metastasis, no longer require corticosteroids, and are asymptomatic; subjects with neurological symptoms should undergo a head computed tomography (CT) scan or brain magnetic resonance imaging (MRI) to exclude brain metastasis, at the discretion of the treating physicianXx_NEWLINE_xXParticipants 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)Xx_NEWLINE_xXHistory 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 studyXx_NEWLINE_xXPatients with symptomatic brain metastasis requiring escalating doses of steroidsXx_NEWLINE_xXHas no evidence of new or enlarging brain metastases confirmed by post-treatment repeat brain imaging performed ?3 weeks after pre-treatment brain imaging, andXx_NEWLINE_xXSubjects with previously treated progressing brain metastases are excluded from the studyXx_NEWLINE_xXSubjects with known brain metastases and contraindications to undergo contrast MRI imaging of the brain are excluded from the studyXx_NEWLINE_xXSymptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroidsXx_NEWLINE_xXPreviously documented or current brain metastases.Xx_NEWLINE_xXSubjects with symptomatic uncontrolled brain metastases;Xx_NEWLINE_xXNo history of distant metastases.Xx_NEWLINE_xXUntreated brain metastasesXx_NEWLINE_xXPrimary brain tumors or CNS metastases;Xx_NEWLINE_xXParticipants 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 treatmentXx_NEWLINE_xXPatients 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 drugXx_NEWLINE_xXEvidence of distant metastasesXx_NEWLINE_xXPatients 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 stableXx_NEWLINE_xXPatients with known active or symptomatic brain metastases prior to vaccination.Xx_NEWLINE_xXPatients with known brain metastases should be excluded as this would qualify as stage IV/metastatic diseaseXx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXAdditional unresected brain metastases (up to 2) must have a maximum diameter of less than or equal to 3 cmXx_NEWLINE_xXPatients 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 registrationXx_NEWLINE_xXBrain metastasesXx_NEWLINE_xXBrain metastases or spinal cord compression, unless treated at least 4 weeks before first dose and stable without steroid treatment for 10 daysXx_NEWLINE_xXPatients with known symptomatic brain metastases requiring steroids.Xx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXKnown brain metastasisXx_NEWLINE_xXMetastatic brain or meningeal tumors (symptomatic or asymptomatic).Xx_NEWLINE_xXPatients 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 steroidsXx_NEWLINE_xXSubjects 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 enrollmentXx_NEWLINE_xXBrain metastasesXx_NEWLINE_xXbrain metastases are stable and have been previously treated with either whole-brain radiotherapy or gamma-knife surgeryXx_NEWLINE_xXSubjects with previously untreated or uncontrolled brain metastases.Xx_NEWLINE_xXActive brain metastases.Xx_NEWLINE_xXKnown brain metastases, uncontrolled seizure disorders, encephalitis, or multiple sclerosisXx_NEWLINE_xXActive 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 weeksXx_NEWLINE_xXPatients 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 excludedXx_NEWLINE_xXHas brain metastases with evolving neurologic symptoms or a steroid requirement.Xx_NEWLINE_xXSymptomatic brain metastases (patients with asymptomatic brain metastases may be eligible provided other criteria are met)Xx_NEWLINE_xXSymptomatic brain metastases.Xx_NEWLINE_xXUncontrolled or severe concurrent medical condition (including uncontrolled brain metastases).Xx_NEWLINE_xXEvidence of distant metastasesXx_NEWLINE_xXPatients with known brain metastases unless treated with an appropriate modality with no evidence of progression/recurrence for > 3 monthsXx_NEWLINE_xXPatients with brain metastases are eligible if asymptomatic and neurologically stable for at least 4 weeks and are not taking any medications contraindicatedXx_NEWLINE_xXPatients 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 protocolXx_NEWLINE_xXHistory of brain metastases unless irradiated ? 2 weeks prior to first study treatment and stable without requirement of corticosteroids.Xx_NEWLINE_xXSubjects who have new or progressive brain or meningeal or spinal metastasesXx_NEWLINE_xXActive 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 administrationXx_NEWLINE_xXActive metastases.Xx_NEWLINE_xXActive brain metastases (e.g. stable for < 4 weeks, no adequate previous treatment with radiotherapy, symptomatic, requiring treatment with anti-convulsants; dexamethasone therapy will be allowed if administered as stable dose for at least one month before randomization)Xx_NEWLINE_xXUncontrolled or severe concurrent medical condition (including uncontrolled brain metastases).Xx_NEWLINE_xXDocumented evidence of distant metastases or brain metastasesXx_NEWLINE_xXKnown brain metastases.Xx_NEWLINE_xXSymptomatic metastatic brain or meningeal tumorsXx_NEWLINE_xXSubject has known brain metastases.Xx_NEWLINE_xXBrain metastases, or spinal cord compression. Individuals with brain metastases are allowed if they have been treated with irradiation or surgery, are clinically stable without steroid treatment. Individuals with documented leptomeningeal disease are not eligible.Xx_NEWLINE_xXSymptomatic metastatic brain or meningeal tumorsXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXSymptomatic brain metastasesXx_NEWLINE_xXSymptomatic brain metastasesXx_NEWLINE_xXSymptomatic brain metastases.Xx_NEWLINE_xXSymptomatic brain metastases.Xx_NEWLINE_xXBrain 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 screeningXx_NEWLINE_xXSymptomatic metastatic brain or meningeal tumors; baseline brain imaging is not requiredXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients 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 investigatorXx_NEWLINE_xXBrain metastasis unless treated and neurologically stableXx_NEWLINE_xXSubjects 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 therapyXx_NEWLINE_xXSubjects with leptomeningeal metastases may or may not have brain metastases. When brain metastases are present, they do not need to have progressed after radiation therapyXx_NEWLINE_xXThe 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 eligibilityXx_NEWLINE_xXClinically active brain metastasesXx_NEWLINE_xXSymptomatic brain metastasis or asymptomatic brain metastasis that are 1 cm or greater in size; patients with asymptomatic sub-centimeter brain metastasis are eligibleXx_NEWLINE_xXBrain metastases requiring steroidsXx_NEWLINE_xXKnown brain metastases, or untreated meningeal/dural diseaseXx_NEWLINE_xXBrain biopsy or resection;Xx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients with known brain metastases are excluded from this studyXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients 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 metastasesXx_NEWLINE_xXKnown brain, leptomeningeal or epidural metastases (unless treated and well controlled for at least 3 months)Xx_NEWLINE_xXSubjects with known or suspected brain metastases, primary brain tumors, or brain as the only site of diseaseXx_NEWLINE_xXPatients 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 indicatedXx_NEWLINE_xXBrain metastases requiring steroids.Xx_NEWLINE_xX10. 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.Xx_NEWLINE_xXUntreated 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.)Xx_NEWLINE_xXUncontrolled or severe concurrent medical condition (including uncontrolled brain metastases).Xx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXAt 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 MRIXx_NEWLINE_xXThe 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)Xx_NEWLINE_xXHas active brain metastasis or leptomeningeal carcinomatosis; patients with adequately treated brain metastases are eligible if they meet certain criteriaXx_NEWLINE_xXPatients 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 eventsXx_NEWLINE_xXKnown brain metastasis; patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasisXx_NEWLINE_xXPatients must have no clinical evidence of active brain metastasis. Patients with a history of brain metastases must meet all of the following criteria:Xx_NEWLINE_xXHistory or clinical evidence of brain metastasesXx_NEWLINE_xXPatients 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 treatmentXx_NEWLINE_xXPatients 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 investigatorXx_NEWLINE_xXPatients who are taking bevacizumab or have taken bevacizumab within the past 2 weeks for treatment of their brain metastasesXx_NEWLINE_xXPatients with brain metastases are allowed only if they are off systemic corticosteroids and stable for a minimum of 8 weeksXx_NEWLINE_xXHas known untreated or symptomatic brain metastases;Xx_NEWLINE_xXPatients 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 armsXx_NEWLINE_xXPresence 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 enrollmentXx_NEWLINE_xXPatients with known brain metastasesXx_NEWLINE_xXParticipants with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients with more than a single brain metastasis ( >1 cm)Xx_NEWLINE_xXActive 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 treatmentXx_NEWLINE_xXPatients may not have symptomatic, uncontrolled spinal cord compression and/or brain metastases; a scan to confirm absence of brain metastasis is not required; patients can receive a stable dose of corticosteroids before/ during study if these were started at least 28 days prior to entryXx_NEWLINE_xXPatients 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 registrationXx_NEWLINE_xXUntreated brain metastasis; patients with treated brain metastases who are off steroids are eligibleXx_NEWLINE_xXPatients 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 investigatorXx_NEWLINE_xXThe 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 eligibilityXx_NEWLINE_xXActive brain metastases or leptomeningeal metastasesXx_NEWLINE_xXKnown brain metastasis.Xx_NEWLINE_xXPresence 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.Xx_NEWLINE_xXPatients with known brain metastasesXx_NEWLINE_xXPatients with brain metastases which are stable and have been treated with surgery or irradiation will be eligible for this trialXx_NEWLINE_xXPatients 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)Xx_NEWLINE_xXKnown brain metastasisXx_NEWLINE_xXUntreated brain metastasesXx_NEWLINE_xXDocumented primary brain malignancy or brain metastases.Xx_NEWLINE_xXPatients 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 enrollmentXx_NEWLINE_xXParticipant with a brain metastasis with symptoms or requiring treatment.Xx_NEWLINE_xXHistory of spinal cord compression or brain metastases, unless asymptomatic, treated, stable, and not requiring treatment with steroids for at least 4 weeks before the planned administration of the first dose of study drug. Any history of leptomeningeal metastases.Xx_NEWLINE_xXKnown brain metastases that are untreated, symptomatic, or require therapy to control symptomsXx_NEWLINE_xXBrain metastasisXx_NEWLINE_xXSubject has known brain metastasesXx_NEWLINE_xXRecurrent brain metastases from breast cancerXx_NEWLINE_xXSubjects 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 allowedXx_NEWLINE_xXSymptomatic uncontrolled brain metastasisXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXSymptomatic brain metastasesXx_NEWLINE_xXBrain 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             randomizationXx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXPatients 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 eligibilityXx_NEWLINE_xXPatients with active brain metastases should be excluded from this clinical trial except as noted aboveXx_NEWLINE_xXSymptomatic central nervous system metastases; subjects with brain metastases that have been previously treated and are stable for 4 weeks are allowedXx_NEWLINE_xXEvidence 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 diagnosisXx_NEWLINE_xXKnown 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.Xx_NEWLINE_xXPatients with untreated central nervous system metastases or local treatment of brain metastasesXx_NEWLINE_xXSubject 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.Xx_NEWLINE_xXUncontrolled 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])Xx_NEWLINE_xXPatients with known brain metastases will be excluded from this clinical trialXx_NEWLINE_xXEvidence 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.Xx_NEWLINE_xXPatients who are symptomatic from brain metastasisXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXBrain metastasesXx_NEWLINE_xXKnown brain metastases; patients with known brain metastases must be excluded from this clinical trialXx_NEWLINE_xXPatients with known brain metastases will be excludedXx_NEWLINE_xXDocumented metastases to brain or meninges.Xx_NEWLINE_xXSpinal cord compression or brain metastases unless asymptomatic and not requiring steroids for at least 4 weeksXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXUntreated brain metastases; brain metastases =< 1 cm and not associated with any focal neurologic deficits are allowedXx_NEWLINE_xXSymptomatic brain metastasis. Participants with brain metastases:Xx_NEWLINE_xXActive brain or subdural metastasesXx_NEWLINE_xXPatients 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 metXx_NEWLINE_xXAny known symptomatic brain metastases requiring steroids.Xx_NEWLINE_xXPatients with symptomatic brain metastasis requiring escalating doses of steroidsXx_NEWLINE_xXPatient with brain metastases that are symptomatic and/or require therapy.Xx_NEWLINE_xXPatients 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 daysXx_NEWLINE_xXPatients with known symptomatic brain metastases requiring steroidsXx_NEWLINE_xXActive or progressing brain metastasesXx_NEWLINE_xXPatients with a prior history of seizures within the past year unrelated to brain metastasesXx_NEWLINE_xXPatients 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 enrollmentXx_NEWLINE_xXSubjects 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.Xx_NEWLINE_xXBrain metastases requiring steroidsXx_NEWLINE_xXHas 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).Xx_NEWLINE_xXUntreated brain metastasesXx_NEWLINE_xXBrain 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 treatmentXx_NEWLINE_xXActive, untreated brain metastasesXx_NEWLINE_xXPatients who previously had brain metastases (screening not required) unless they have met all of the following criteria:Xx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXBrain metastases are allowed if the patient is asymptomatic or previous steroid treatment was discontinued >= 6 weeksXx_NEWLINE_xXUncontrolled 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 allowedXx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXPatients with prior whole brain irradiationXx_NEWLINE_xXSymptomatic or untreated leptomeningeal or brain metastases or spinal cord compression; treated brain metastases must have been stable for at least 1 monthXx_NEWLINE_xXUntreated brain metastasesXx_NEWLINE_xXFor 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.Xx_NEWLINE_xXSymptomatic or untreated brain metastases or spinal cord compression or any of these conditions requiring chronic steroids to control symptoms.Xx_NEWLINE_xXKnown brain metastases (systematic screening of patients not mandatory)Xx_NEWLINE_xXPatients 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)Xx_NEWLINE_xXKnown parenchymal brain metastasisXx_NEWLINE_xXThe patient has a primary brain tumor. Patients may have brain metastases from another primary site.Xx_NEWLINE_xXPresence of serious illnesses or medical condition(s) e.g. brain metastases, systemic infection, heart failureXx_NEWLINE_xXPatients with known brain metastasisXx_NEWLINE_xXEvidence of uncontrolled brain metastases or history of uncontrolled seizures.Xx_NEWLINE_xXSubject 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).Xx_NEWLINE_xXSymptomatic metastatic brain or meningeal tumorsXx_NEWLINE_xXKnown active, or symptomatic, brain metastasisXx_NEWLINE_xXPatients with known brain metastasesXx_NEWLINE_xXBrain 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 studyXx_NEWLINE_xXPatients 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 treatmentXx_NEWLINE_xXPatients with known brain metastases will be excluded from this portion of the clinical trial (which will assess PFS and TTP)Xx_NEWLINE_xXPatients with brain or leptomeningeal metastases are allowed on study if the lesions are asymptomatic without neurological signs and clinically stable for at least 2 weeksXx_NEWLINE_xXCurrent or a prior history of brain metastases or leptomeningeal disease. Must not have rapidly progressive, life-threatening metastases.Xx_NEWLINE_xXPresence of any brain metastases detected by MRI or CT with i.v. contrast of the brain at screening.Xx_NEWLINE_xXActive or progressing brain metastasesXx_NEWLINE_xXBrain metastasis are excluded unlessXx_NEWLINE_xXThe 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).Xx_NEWLINE_xXKnown 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 excludedXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients with primary brain cancer or known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXActive brain metastasesXx_NEWLINE_xXPatient 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 trialXx_NEWLINE_xXPatients with known brain metastasesXx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXPatients with known untreated brain metastasesXx_NEWLINE_xXUncontrolled brain metastasesXx_NEWLINE_xXKnown or suspected metastases in the brainXx_NEWLINE_xXUncontrolled 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.Xx_NEWLINE_xXPatients with known brain metastases are excluded from this clinical trialXx_NEWLINE_xXAny 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.Xx_NEWLINE_xXSubjects with CNS symptoms should undergo a CT scan or MRI of the brain to exclude new or progressive brain metastases. Spinal cord metastasis is acceptable. However, subjects with spinal cord compression should be excluded.Xx_NEWLINE_xXKnown brain metastasisXx_NEWLINE_xXPatients 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 eligibilityXx_NEWLINE_xXRadiologic evidence of new and/or progressive brain metastasis (>= 10 mm in longest dimension) by magnetic resonance (MR) imaging of the brainXx_NEWLINE_xXKnown 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 eligibilityXx_NEWLINE_xXSpinal cord compression or brain metastases unless asymptomatic, treated and stable (not requiring steroids).Xx_NEWLINE_xXHistory of or known presence of brain or spinal cord metastasesXx_NEWLINE_xXActive or untreated brain metastasesXx_NEWLINE_xXParticipants with primary brain tumors or disease metastatic to the brain.Xx_NEWLINE_xXPatients 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 studyXx_NEWLINE_xXParticipants with known brain metastases that are symptomatic and require corticosteroids are excludedXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPresence of brain metastasesXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXKnown or suspected brain metastasis;Xx_NEWLINE_xXKnown brain metastases that are untreated, symptomatic, or require therapy to control symptomsXx_NEWLINE_xXBrain metastases with symptoms or requiring treatmentXx_NEWLINE_xXKnown brain metastasisXx_NEWLINE_xXKnown central nervous system (CNS) or brain metastasis that are either symptomatic or untreated; Note: patients with neurological symptoms must undergo a computed tomography (CT) scan/magnetic resonance imaging (MRI) of the brain to exclude brain metastasis\r\n* Note: patients with CNS metastases that have been treated and are stable without symptoms for >= 4 weeks after completion of treatment are eligibleXx_NEWLINE_xXPatients with untreated brain metastases should be excluded from this clinical trialXx_NEWLINE_xXHistologically confirmed initial diagnosis of primary WHO Grade IV malignant glioma (glioblastoma), now recurrent; or Cohorts 2 and 3 only: progressive secondary brain tumor, has failed standard brain radiotherapy, and has brain tumor progression after at least one line of systemic therapy. Patients with progressive secondary brain tumors will not be enrolled under this protocol following the completion of Cohort 3.Xx_NEWLINE_xXSubjects with known or suspected brain metastasis unless previously treated and without evidence of progressionXx_NEWLINE_xXKnown history or evidence of brain metastasesXx_NEWLINE_xXSubjects with brain metastasesXx_NEWLINE_xXSymptomatic and progressive or corticosteroid-requiring documented brain metastasesXx_NEWLINE_xXUp to 2 additional intact brain metastases to be treated with stereotactic radiosurgery (SRS) aloneXx_NEWLINE_xXFirst presentation of brain metastasesXx_NEWLINE_xXPrevious brain radiotherapy (SRS or whole brain radiation therapy [WBRT])Xx_NEWLINE_xXPatients with known brain metastases will be excluded from this clinical trialXx_NEWLINE_xXPatients must be free of brain metastasis by contrast-enhanced CT/magnetic resonance imaging (MRI) scans within 4 weeks prior to enrollment; if known to have prior brain metastases, must not have evidence of active brain disease after definitive therapy (surgery, radiation therapy, or stereotactic radiosurgery) on two successive MRI evaluations at least 3 months apart (one of which is =< 4 weeks prior to starting the study drugs)Xx_NEWLINE_xXPatients with brain metastases should be excluded from this clinical trial except as noted aboveXx_NEWLINE_xXKnown brain or spinal cord metastases unless adequately treated (surgery or radiotherapy) with no evidence of progression and neurologically stable off anticonvulsants and steroids.Xx_NEWLINE_xXUncontrolled 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 monthsXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXUntreated brain metastases (or local treatment of brain metastases within the last three months)Xx_NEWLINE_xXIf patient has history of brain metastases, brain lesions should have been treated with surgery and/or radiation and be stable on repeat imaging and patients should be neurologically stable on a stable or tapering dose of corticosteroidsXx_NEWLINE_xXUntreated brain metastasesXx_NEWLINE_xXSymptomatic brain metastasis; patients with treated brain metastasis must be completely weaned off of steroid therapy for at least 14 days prior to starting protocol therapyXx_NEWLINE_xXKnown brain metastasis; patients with neurological symptoms must undergo a computed tomography (CT) scan/MRI of the brain to exclude brain metastasisXx_NEWLINE_xXPatients 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 excludedXx_NEWLINE_xXFor lung metastases, no more than 2 metastases treated in one settingXx_NEWLINE_xXNo active brain metastases. Patients with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis within 30 days prior to registration on protocol therapy. NOTE: A patient with prior brain metastasis are eligible if they have completed their radiation treatment for brain metastasis ?30 days prior to registration for protocol therapy, are off steroids, and are asymptomatic.Xx_NEWLINE_xXPresence of clinically apparent or suspected brain metastasis.Xx_NEWLINE_xXKnown brain metastasis or visceral organ metastasisXx_NEWLINE_xXSubjects may have distant metastasis, including brain metastases. Subjects with known brain metastases are eligible if:Xx_NEWLINE_xXThey have received standard anti-tumor treatment for their brain metastases without encephalopathy;Xx_NEWLINE_xXKnown brain metastases (scan required at screening)Xx_NEWLINE_xXMetastases in the brain or active epidural disease. (Note: patients with treated epidural disease are allowed);Xx_NEWLINE_xXBrain stem involvement allowedXx_NEWLINE_xXBrain lesions with a propensity to bleedXx_NEWLINE_xXPatients with known brain metastases are excluded from this clinical trialXx_NEWLINE_xXPatients 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 administrationXx_NEWLINE_xXBrain 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 entryXx_NEWLINE_xXPrior whole brain irradiationXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients 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 enrollmentXx_NEWLINE_xXPatients with brain metastases are excludedXx_NEWLINE_xXPatients 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 drugsXx_NEWLINE_xXSymptomatic, 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)Xx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients 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 excludedXx_NEWLINE_xXUncontrolled 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])Xx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXPatients 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 eligibleXx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXStable, 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 drugXx_NEWLINE_xXPrior surgical resection for brain metastasesXx_NEWLINE_xXPatients with 1-10 newly diagnosed brain metastasesXx_NEWLINE_xXPatient has evidence of clinically unstable brain metastases (controlled and stable brain metastasis must be previously treated and asymptomatic)Xx_NEWLINE_xXNo 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 carcinomatosisXx_NEWLINE_xXPatients 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 gliomasXx_NEWLINE_xXHave distant metastasesXx_NEWLINE_xXPresence 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 enrollmentXx_NEWLINE_xXPatient 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)Xx_NEWLINE_xX1 to 10 brain metastases (mets) (no more than two lesions and/or cavities >= 3 cm in maximum diameter)Xx_NEWLINE_xXPatients will be excluded if they have brain metastasisXx_NEWLINE_xXPatients with known brain metastases;Xx_NEWLINE_xXKnown 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 physicianXx_NEWLINE_xXSubjects with active brain metastases or leptomeningeal metastasesXx_NEWLINE_xXSubject 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.Xx_NEWLINE_xXParticipants with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXBrain metastases that are symptomatic or untreated or that require current therapy.Xx_NEWLINE_xXPatients with known distant metastases or other malignanciesXx_NEWLINE_xXPresence of brain metastasesXx_NEWLINE_xXPatients with brain tumorsXx_NEWLINE_xXPatients 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 registrationXx_NEWLINE_xXMetastases to the brainXx_NEWLINE_xXBrain metastasisXx_NEWLINE_xXPrimary brain tumorsXx_NEWLINE_xXMetastases to the brainXx_NEWLINE_xXPrimary brain cancer (presumed gliomas with no radiographic or clinical evidence of metastatic disease to the brain)Xx_NEWLINE_xXSUBJECT: Must be at least 1 year post completion of radiation therapy to the brain or brain and spine.Xx_NEWLINE_xXDistant metastasesXx_NEWLINE_xXParticipant had breast cancer with brain metastasesXx_NEWLINE_xXPatients with history of epilepsy, brain damage, use of anti-convulsants for seizure prevention, concurrently using ketamine, symptomatic brain metastases; note: anti-convulsant use is allowed for neuropathy and heart failure (HF) if on a stable doseXx_NEWLINE_xXPrevious neurosurgery on the brainXx_NEWLINE_xXNo clinical neurologic signs or symptoms of brain metastasis (brain imaging only required for symptomatic individuals per 2014 National Comprehensive Cancer Network [NCCN] Guidelines)Xx_NEWLINE_xXParticipants with known brain metastasesXx_NEWLINE_xXPatients with known brain metastases will be excluded from this clinical trialXx_NEWLINE_xXNo definitive evidence of brain metastases on brain computed tomography (CT) scan or brain magnetic resonance imaging (MRI) < 1 month prior to study entryXx_NEWLINE_xXRadiographic evidence of brain metastases and/or ipsilateral lung metastases/malignant pleural effusionXx_NEWLINE_xXMetastases to the brainXx_NEWLINE_xXBrain 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 hippocampusXx_NEWLINE_xXHistory of epilepsy, brain damage, use of anticonvulsants for seizure prevention, concurrently using ketamine, symptomatic brain metastasesXx_NEWLINE_xXPatients with known brain metastases, history of brain metastases or radiation to the brain.Xx_NEWLINE_xXPatients with history of epilepsy, brain damage, or symptomatic brain metastases.Xx_NEWLINE_xXSymptomatic metastatic brain or meningeal tumorsXx_NEWLINE_xXKnown brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before study enrollment; eligible subjects must be without corticosteroid treatment at the time of study enrollmentXx_NEWLINE_xXSubjects who have new or progressive brain or meningeal or spinal metastases.Xx_NEWLINE_xXUntreated 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 drugXx_NEWLINE_xXActive 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 administrationXx_NEWLINE_xXPatients 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 imagingXx_NEWLINE_xXPatients 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)Xx_NEWLINE_xXParticipant has untreated brain or meningeal metastases.Xx_NEWLINE_xXAny past neurologic insult that is known to affect brain function such as traumatic brain injury, dementia, encephalopathy, etc.Xx_NEWLINE_xXSymptomatic and/or untreated brain metastasesXx_NEWLINE_xXPatients with “treated and stable” brain lesions of a duration of >= 2 months may be enrolledXx_NEWLINE_xXPatient must not have brain metastases present prior to initiation of initial therapy or PCIXx_NEWLINE_xXSubjects with a history of brain metastasis.Xx_NEWLINE_xXHas distant metastasesXx_NEWLINE_xXPatients must have a magnetic resonance imaging (MRI) or CT brain within 4 weeks prior to study entry to rule out asymptomatic brain metastasesXx_NEWLINE_xXActive central nervous system (CNS) metastases; patients with neurological symptoms should undergo a head computed tomography (CT) scan or brain magnetic resonance imaging (MRI) to exclude brain metastasis, at the discretion of the treating physician; NOTE: patients with prior brain metastasis may be considered if they have completed their treatment for brain metastasis, no longer require corticosteroids, and are asymptomaticXx_NEWLINE_xXPatients with known distant metastases or other malignanciesXx_NEWLINE_xXHave clinical evidence of lymphedema, current bowel obstruction, or symptomatic brain metastases, as determined by their treating oncologist.Xx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXParticipants with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXPatients with brain metastases are allowed on this study (concurrent treatment with steroids is allowed)Xx_NEWLINE_xXMetastatic cancer to the brain for which palliative whole brain radiotherapy is recommended.Xx_NEWLINE_xXDiagnosis of primary brain tumorsXx_NEWLINE_xXKnown history of brain metastasesXx_NEWLINE_xXSubjects 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.Xx_NEWLINE_xXKnown brain metastasisXx_NEWLINE_xXPatients with known symptomatic brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients with active CNS or other brain metastasesXx_NEWLINE_xXParticipants with symptomatic uncontrolled brain metastases; a scan to confirm the absence of brain metastases is not requiredXx_NEWLINE_xXPatients 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 CYP3A4Xx_NEWLINE_xXAny 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 treatedXx_NEWLINE_xXPatients with brain metastases are allowed onto the study as long as patients have completed their treatment for brain metastasis, no longer require corticosteroids, and are asymptomatic; subjects with neurological symptoms should undergo a head computed tomography (CT) scan or brain magnetic resonance imaging (MRI) to exclude brain metastasis, at the discretion of the treating physicianXx_NEWLINE_xXPatient has not received any previous brain RT.Xx_NEWLINE_xXNo history of seizures related to the brain metastases or LMD.Xx_NEWLINE_xXParticipants with known brain metastases, or any other metastases from cancerXx_NEWLINE_xXBrain metastases requiring focal or whole brain radiation will be excludedXx_NEWLINE_xXRadiologic evidence of new and/or progressive brain metastases (>= 10 mm in longest dimension) by MRI imaging of the brainXx_NEWLINE_xXPrior brain tumor treatment, including surgical resection, radiation therapy or chemotherapy for a primary brain neoplasm. Previous biopsy will not disqualify the patient from participation. Remote history (> 6 month) of non-CNS malignancy in remission, without evidence of current/ prior brain metastasis, will also not disqualify patient from participating.Xx_NEWLINE_xXHas 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 allowedXx_NEWLINE_xXDistant metastasesXx_NEWLINE_xXPrior brain cancerXx_NEWLINE_xXParticipants with known brain metastases will be excluded from this clinical trialXx_NEWLINE_xXPatients with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXPatients 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 progressionXx_NEWLINE_xXEvidence for hemorrhage within any of the brain metastases.Xx_NEWLINE_xXParticipants with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXParticipants with known brain metastases should be excluded from this clinical trialXx_NEWLINE_xXKnown brain metastasisXx_NEWLINE_xXPatient 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)Xx_NEWLINE_xXBrain metastasesXx_NEWLINE_xXAIM 3: Patients with either cutaneous, visceral or brain melanoma metastasesXx_NEWLINE_xXHas 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)Xx_NEWLINE_xXUntreated 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.Xx_NEWLINE_xXNo evidence of CNS disease by MRI or CT of the brain. Note: Prior brain metastasis which have been treated with definitive therapy are eligible.Xx_NEWLINE_xXSubject has known history of brain metastases.Xx_NEWLINE_xXHistologically 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.Xx_NEWLINE_xXParticipants with known uncontrolled brain metastasesXx_NEWLINE_xXBrain 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)Xx_NEWLINE_xXPatients 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 metastasesXx_NEWLINE_xXPatients 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 metastasesXx_NEWLINE_xXPatients presenting with brain tumors will be eligible for this studyXx_NEWLINE_xXParticipants 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 studyXx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXPatients with symptomatic brain metastases are excluded from this study.Xx_NEWLINE_xXPatients with brain metastasis that have been treated, asymptomatic and off any steroid use are permitted for studyXx_NEWLINE_xXKnown brain metastasesXx_NEWLINE_xXAll 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 trabectedinXx_NEWLINE_xXActive or progressing brain metastasesXx_NEWLINE_xXPatients with known brain metastasesXx_NEWLINE_xXUntreated brain metastasesXx_NEWLINE_xXClinically 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).Xx_NEWLINE_xXPresence of gliomas and brain metastases only if neurologically stable and treated without ongoing requirement for corticosteroids for at least 2 weeks.Xx_NEWLINE_xXBrain metastases allowed if asymptomatic, without edema, and not receiving corticosteroids or radiationXx_NEWLINE_xXThe 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)Xx_NEWLINE_xXHas 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.Xx_NEWLINE_xXKnown Stage IV ovarian cancer with Brain MetastasesXx_NEWLINE_xXKnown brain metastases that are untreated, symptomatic, or require therapy to control symptomsXx_NEWLINE_xXPatients with local regional recurrence only or brain only metastasis.Xx_NEWLINE_xXSubjects with detectable cerebrospinal fluid malignant cells or brain metastases or with a history of cerebrospinal fluid malignant cells or brain metastasesXx_NEWLINE_xXPatients with primary brain tumors or primary tumors with central nervous system metastases as only location of disease. Controlled brain metastases are permittedXx_NEWLINE_xXHas active brain metastases or leptomeningeal metastases.Xx_NEWLINE_xXSubjects with any evidence of distant metastasesXx_NEWLINE_xXParticipants must not have symptomatic brain metastases or brain metastases requiring steroids; asymptomatic brain metastases not requiring steroids are acceptableXx_NEWLINE_xXBrain 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.Xx_NEWLINE_xXBrain metastases have been treated.Xx_NEWLINE_xXPatients 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 investigatorXx_NEWLINE_xXParticipants 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.Xx_NEWLINE_xXPatients 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 metastasesXx_NEWLINE_xXHistory of brain involvement with cancer, spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease. Patients with radiated or resected lesions are permitted, provided the lesions are fully treated and inactive, patients are asymptomatic, and no steroids have been administered for brain edema for at least 28 daysXx_NEWLINE_xXBrain 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.Xx_NEWLINE_xXSymptomatic brain metastasesXx_NEWLINE_xXPatients 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.Xx_NEWLINE_xXPatient 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.Xx_NEWLINE_xX