Patients with brain metastases or primary brain tumors must have completed treatment, surgery or radiation therapy >= weeks prior to start of treatment Patients with brain metastases or primary brain tumors must have completed treatment, surgery or radiation therapy >= 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 days prior to registration; patients must have a CT or MRI scan of the brain to evaluate for central nervous system (CNS) disease within days prior to registration Patients with known brain metastases must either meet the additional criteria and enroll as part of the Progressive Brain Metastases Cohort, or have clinically controlled neurologic symptoms, defined as surgical excision and/or radiation therapy followed by days of stable neurologic function prior to registration; patients with previously incidentally discovered or asymptomatic brain metastasis(es) must receive surgical excision and/or radiation therapy prior to registration; patients with progressive brain metastases following prior treatment are not eligible for the Standard Cohort, but may be considered for the Progressive Brain Metastases Cohort Progressive Brain Metastases Cohort\r\n* S 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 days prior to trial registration will be in the Standard Cohort and may obtain MRI of the brain at the physicians 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 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 days prior to registration; brain metastases must be progressive and >= 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 >= days prior to registration\r\n** If patient had an open brain biopsy, at least days must have elapsed between biopsy and registration\r\n** Patients enrolling in the Progressive Brain Metastases Cohort can have received up to prior lines of cytotoxic chemotherapy for metastatic disease; note that for enrollment in the standard cohort, patients must have had =< prior cytotoxic regimen for metastatic disease Patients with no known brain metastasis must have baseline brain imaging within weeks prior to study registration not demonstrating brain metastases OR Patients with known brain metastases must have baseline brain imaging within 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) >= weeks prior to registration, or have undergone complete neurosurgical resection >= months prior to registration\r\n* Be clinically stable from brain metastases at time of screening, if no treatment was administered\r\n* Known leptomeningeal disease is not allowed Patients must have had no prior radiation therapy with the exception of CNS irradiation of brain metastases; (this exception only applies to SR patients; any patients over age with distant metastases to brain [stage IV disease] would be considered poor risk and therefore not eligible for this trial) Prior radiotherapy for patients with brain metastases prior to enrollment is acceptable. At least measurable unirradiated parenchymal brain metastasis within days prior to study entry; patients who are to undergo SRS must have no more than brain metastases; there is no limit on number of brain metastases for WBRT; the minimum size as measured on T-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 >= mm\r\n* For or more lesions, the size of at least of the lesions must be >= 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 - brain metastases, with at least new measurable brain lesion\r\n** Progressive parenchymal brain metastasis following surgical resection of - brain metastases, with at least measurable brain lesion No radiation therapy (other than to the brain) within days of day of protocol chemotherapy except radiation to brain metastases, which must be completed days prior to start of chemotherapy No large (>= cm) hemorrhagic or symptomatic brain metastases until local treatment has been administered (radiation therapy or surgery); treatment may begin >= days after completion of local treatment; patients with small (< cm) and asymptomatic brain metastases are allowed and may be treated with radiation therapy and/or surgery concurrently with Arm A or cycles and of Arm B if deemed medically indicated; radiation therapy should not be given concurrently with high-dose carboplatin or etoposide Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms; participants with previously diagnosed brain metastases are eligible if they have completed treatment at least one month prior to trial therapy initiation, are neurologically stable with an absence of new neurological symptoms for at least 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 >= 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 Participants with CNS metastases are not eligible, unless they have completed local therapy (eg, whole brain radiation therapy [WBRT], surgery or radiosurgery) and have discontinued the use of corticosteroids for this indication for at least weeks before starting treatment in this study. Any signs (eg, radiologic) or symptoms of brain metastases must be stable for at least weeks before starting study treatment Will need immediate local surgery or radiation for their brain metastases Subjects with ? brain metastases and each ? cm size that were treated with either surgical resection and/or radiation therapy are eligible for study participation provided (a) there is no evidence of progressive central nervous system (CNS) disease on brain imaging at least days after definitive treatment and (b) the subject is not taking prednisone at > mg or equivalent daily. Subjects with > cm or > 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 days after treatment with surgery and/or radiation therapy and (b) if the subject is not taking prednisone at > mg or equivalent daily. Partial brain radiotherapy (i.e. =< % of total brain volume) within the last weeks Whole brain radiotherapy within the last months or partial brain radiotherapy exceeding > % of total brain volume within the last months Prior local therapy:\r\n* Prior surgery, whole brain radiation or SRS is allowed as long as the most recent brain progression is amenable to SRS treatment Participants who have undergone prior radiation for brain metastases; patients who have undergone resection of one or more brain metastases but who have not yet started adjuvant radiotherapy are eligible for the study Participants who have received prophylactic cranial radiation for prevention of brain metastases Or have required any type of major treatment, e.g., whole brain radiation treatment, adjuvant chemotherapy, gamma knife, to control symptoms from brain metastases within days of the first study treatment. Brain lesions or intracranial abnormalities at risk for bleeding, by history or radiologic imaging (e.g., active metastases). Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms; participants with previously diagnosed brain metastases are eligible if they have completed treatment at least 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 >= weeks before the initiating protocol therapy; treatment for brain metastases may include surgery, whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating physician Participants who have undergone prior radiation for brain metastases; patients who have undergone resection of one or more brain metastases but who have not yet started adjuvant radiotherapy are eligible for the study Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms; participants with previously diagnosed brain metastases are eligible if they have:\r\n* Completed treatment (whole brain radiotherapy, radiosurgery, or a combination) at least 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 >= weeks before prior to registration At least one measurable lesion per RANO-BM (Response Assessment in Neuro-Oncology Brain Metastases) Criteria for brain metastasis Patients with - untreated brain metastases at time of initial brain metastases diagnosis (surgery to one of the brain lesions and/or biopsy of a lesion for diagnostic purposes and/or for standard of care purposes is acceptable) Largest brain metastases volume measures less than . cc^ If they have brain metastases located in the brain stem (including midbrain, pons, or medulla) Patients with known brain metastases will be eligible as long as they have completed radiation to the brain, and have been off of corticosteroid therapy for at least days Patients with leptomeningeal disease are not eligible but patients with brain metastases are eligible these patients should commence treatment on study > week after completion of gamma knife or whole brain radiotherapy or > 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 mg/day of dexamethasone can begin study treatment; and steroids should be tapered off as quickly as clinically feasible; repeat brain magnetic resonance imaging (MRI) after radiation is not required for eligibility but is strongly recommended, to establish the pre-treatment baseline status of any brain metastases, necessary to accurately assess for response or progression; patients with untreated, asymptomatic brain metastasis not requiring steroids are also eligible, however, these patients need to be discussed with the study PI prior to being registered Patients must have between to new or recurrent lesions suspicious for metastatic RCC on diagnostic imaging\r\n* Each extracranial lesion must be =< cm and amenable to SBRT or surgical excision\r\n* Patients must have or fewer brain metastases, of size =< cm\r\n** Brain metastases must be treated prior to enrollment in the study; the modality of treatment of brain metastases can include surgical resection, whole brain radiotherapy, stereotactic radiosurgery, or any combination of the above Patients 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. Patients with brain metastases may be eligible if all of the following are true:\r\n* The total number of brain metastases ever is less than or equal to .\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 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 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 cm in diameter at the time of protocol entry. Patients with known brain metastases are not excluded from this clinical trial. Patients who received palliative radiation (for brain metastases) are eligible if they have been asymptomatic for at least weeks without use of maintenance steroid therapy, and last received radiation at least weeks prior to proposed start of therapy At least one measurable lesion per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) Criteria for brain metastasis Prior systemic therapy is allowed after diagnosis of brain metastases provided that restaging MRI shows measurable intracranial disease Prior radiation treatment to the brain Radiographically confirmed solid tumor brain metastases Previous whole brain radiation therapy Patients with no history of CNS disease will not require a repeat MRI brain unless they have symptoms to suggest new brain metastases Known clinically active brain metastases; prior evidence of brain metastasis successfully treated with surgery or radiation therapy will not be exclusion for participation as long as they are deemed under control at the time of study enrollment and there are no neurological signs of potential brain metastases Patients with history of brain metastases except those with meningeal carcinomatosis or leptomeningeal disease may be eligible for treatment a minimum of week following completion of gamma knife or whole brain radiotherapy, or weeks following surgical resection of brain metastasis provided post-treatment magnetic resonance (MR) scan reveals no evidence of active disease, and no ongoing need for systemic steroids Patients who have a primary brain tumor (excluding meningiomas and other benign lesions), any brain metastases, leptomeningeal disease, seizure disorders not controlled with standard medical therapy, or history of stroke within the past year The total number of tumors requiring SRT must be =< \r\n* Note: Regardless of the number of brain metastases that will be treated with SRT, the brain metastases will be considered to be one tumor Patients with untreated brain metastases; treated brain metastases with radiation or surgery are allowed if: =< cm in size AND =< in number AND there is no evidence of progressive disease, on brain imaging >= days after last day of central nervous system (CNS) treatment Phase II Inclusion Criterion Only: Patients must have - brain metastases, each < cm by contrast MRI, treated within weeks of study entry with SRS and/or resection; a minimum interval of 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 or brain metastases will be evaluated case by case and may be eligible pending on the total field radiated; the presence of concomitant extracranial metastatic disease is allowed for enrollment Subjects with a history of known central nervous system (CNS) metastases must have documentation of stable or improved brain imaging for at least weeks after completion of definitive treatment; definitive treatment may include surgical resection, whole brain irradiation, and/or stereotactic radiation therapy Previous radiation to the brain, including WBRT or brain radiosurgery History of neurologic disorder including but not limited to: prior seizure, epilepsy, structural brain abnormality, benign brain tumor, stroke, brain injuries, dementia, movement disorder or other significant CNS abnormalities Uncontrolled brain metastases; patients treated with radiation >= weeks prior with follow up imaging showing control are eligible Have had prior radiation therapy to the brain or prior treatment for their brain tumor (except prior biopsy or subtotal resection) Patients with active brain metastases should be excluded from this clinical trial; patients with prior history of brain metastasis who have undergone local therapy (i.e., metastasectomy and/or radiation) and show no evidence of local recurrence or progression over the past months are eligible Clinical stability of brain metastases for at least weeks prior to first day of study therapy. Postoperative patients with resected brain metastases are eligible Known clinically active brain metastases; prior evidence of brain metastasis successfully treated with surgery or radiation therapy will not be exclusion for participation as long as they are deemed under control at the time of study enrollment and there are no neurological signs of potential brain metastases More than one brain metastasis (qualifying measurable brain lesions are any contrast enhancing metastases identifiable by the physician) Patients with brain metastases involving the brainstem or chiasm For subjects in cohort (small cell malignancies of non-pulmonary origin), confirmation of no brain metastases via imaging Symptomatic brain metastases; any neurologic symptoms present must have resolved with local therapy by the time of administration of study drug Clinically active brain metastases; radiological documentation of absence of active brain metastases at screening is required for all patients; prior evidence of brain metastasis successfully treated with surgery or radiation therapy will not be exclusion for participation as long as they are deemed under control at the time of study enrollment All brain metastases must be outside the brain stem (midbrain, pons and medulla) Previous treatment with surgery, radiation, chemotherapy, immunotherapy or any targeted agents are allowed provided that:\r\n* Systemic therapy was administered >= days before SRS\r\n* Radiation was not to the brain\r\n* Surgery to the brain was >= days prior to SRS and there remains at least one additional brain metastasis that can be targeted with SRS Patients may have parenchymal brain metastases if stable (no evidence of progression) for at least month after local therapy (radiation or surgery); leptomeningeal disease is excluded; must have completed any prescribed steroid taper prior to registration Patients will have no more than distinct lesions within the brain; at least lesion has been recommended for surgical removal based on size, symptomology, or regional mass effect on the brain PHASE II COLORECTAL CANCER COHORT (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 weeks may be enrolled; baseline imaging to rule out brain metastases is not required for screening, but should be performed prior to study enrollment if clinically indicated Subject 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 . cm in short axis dimension Patients with brain metastasis will be included as long as they are free of neurologic symptoms related to metastatic brain lesions and who do not require or receive systemic corticosteroid therapy in the days prior to beginning MK- therapy Gliomas are excluded, as well as any history of brain metastases, seizures or underlying brain injury Patients with brain metastasis will be included as long as they are free of neurologic symptoms related to metastatic brain lesions and who do not require or receive systemic corticosteroid therapy in the days prior to beginning ipilimumab therapy Patients who have a primary brain tumor (excluding meningiomas and other benign lesions), any brain metastases, leptomeningeal disease, seizure disorders not controlled with standard medical therapy, history of stroke within the past year Prior whole brain radiation therapy (WBRT) Patients with brain metastases may participate in this clinical study provided that symptoms have been controlled with standard therapies and/or appropriate medications; the principal investigator (P.I.) will carefully evaluate the suitability of patient participation when brain metastases are present Untreated, symptomatic, or progressive brain metastases; participants must have no radiographic or other signs of progression in the brain for >= month after completion of local therapy; any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= weeks prior to first study treatment Any patient undergoing SRS for brain metastases Patients may have had prior therapy including:\r\n* Whole brain radiation therapy (WBRT) > months ago\r\n* SRS to other brain metastases Clinically active brain metastases; radiological documentation of absence of active brain metastases at screening is required for all patients; prior evidence of brain metastasis successfully treated with surgery or radiation therapy will not be exclusion for participation as long as they are deemed under control at the time of study enrollment At least days passed since last brain surgery or radiation therapy. Prior radiation to the brain Patients with rapidly advancing parenchymal brain metastases (Cohort D) Uncontrolled brain metastases or treatment by neurosurgical resection or brain biopsy within weeks prior to Day . Any history of intracerebral arteriovenous malformation, cerebral aneurysm, brain metastases or stroke. Tumor location on both sides of the brain and/or involvement that would present the risk of injecting DNX- into the ventricles of the brain Patients must have a histologic diagnosis of melanoma either from a primary or metastatic site; patients with brain metastases must have completed radiation therapy > days prior to enrollment Brain metastases per MRI or CT at any time prior to registration; NOTE: patients that have had primary therapy for brain metastasis (i.e. surgical resection, whole brain radiation, or stereotactic radiotherapy [SRT] even if stable) are not eligible Resection of brain metastases, otherwise untreated with radiation for those brain lesions (presenting for postoperative consolidative radiotherapy) Patient may have received previous treatment for the brain tumor(s), including radiation (focal brain radiation, whole brain radiation or stereotactic radiosurgery), surgery or chemotherapy History of symptomatic metastatic brain or meningeal tumors unless the subject is > months from definitive therapy and has no evidence of tumor growth on an imaging study within 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 screening History of another malignancy that makes determination of the source of the brain metastases uncertain Unable to reliably be immobilized for safe administration of whole brain radiation therapy At least one measurable lesion in the brain (>= mm on T-weighted, gadolinium-enhanced magnetic resonance imaging [MRI]); (prior neurosurgical resection, whole brain radiation or stereotactic radiation therapy is allowed provided the patient has a measurable CNS progression [at least one new and/or progressive measurable brain metastasis]; measurable or non-measurable extracranial metastases allowed); if the potential participant has received brain radiation there needs to be at least one new and/or progressive measurable brain metastases after radiation is completed; do not consent patients if you are planning on administering brain radiation therapy Prior radiation for bone or brain metastases is permitted if patient is now asymptomatic and has completed all radiation and steroid therapy (if applicable) for brain or bone metastases >= weeks prior to study enrollment Symptomatic brain or bone metastases; prior radiation and/or steroid therapy for brain or bone metastases (if applicable) must be completed >= weeks prior to study enrollment Previous whole brain radiation therapy Patients with resected or radiated brain metastases or those treated with stereotactic radiation therapy are eligible, provided they have been off steroids for at least weeks; no history of stroke within the past months Patients with known brain metastases are not eligible; brain imaging studies are not required for eligibility if the patient has no neurologic signs or symptoms suggestive of brain metastasis; but, if brain imaging studies are performed, they must be negative for disease NSCLC subjects with known brain metastases (certain exceptions allowed) History of brain metastases that meet certain conditions; At least one measurable BM by RECIST . criteria (? mm 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 months after the end of WBRT. Subjects with asymptomatic brain metastases may be enrolled without prior radiation therapy to the brain. Subjects with minimally symptomatic brain metastases may be enrolled without prior radiation therapy to the brain if they do not require immediate surgical or radiation therapy in the opinion of the treating investigator and in the opinion of a radiation therapy or neurosurgical consultant Subject has active brain metastases or leptomeningeal metastases. Subjects with prior history of brain metastasis who have undergone local therapy (i.e., metastasectomy and/or radiation) and show no evidence of local recurrence or progression over the past months prior to Screening are eligible. Known clinically active brain metastases; prior evidence of brain metastasis successfully treated with surgery or radiation therapy will not be exclusion for participation as long as they are deemed under control at the time of study enrollment and there are no neurological signs of potential brain metastases Subjects with known or suspected brain metastasis, or brain as the only site of disease are excluded with the following exceptions\r\n* Subjects with controlled brain metastasis (no radiographic progression at least weeks following radiation and/or surgical treatment, off steroids for at least weeks, and have no new or progressing neurological signs or symptoms) will be allowed\r\n* Subjects with a history of prior malignancy with the exception of carcinoma in situ of the cervix or other malignancy diagnosed > years ago that has undergone potentially curative therapy with no evidence of disease for the last >= years and that is deemed by the investigator to be at a low risk of recurrence Any history of intracerebral arteriovenous malformation, cerebral aneurysm, brain metastases or stroke. Patients must not have known brain metastases because the study drug has not been adequately tested in this setting Clinically active brain metastases; radiological documentation of absence of active brain metastases at screening is required for all patients; prior evidence of brain metastasis successfully treated with surgery or radiation therapy will not be exclusion for participation as long as they are deemed under control at the time of study enrollment Prior radiation therapy to the brain is allowed with the exception of whole brain irradiation Patients with known brain metastases will be eligible as long as they have completed radiation to the brain and have been off of corticosteroid therapy for at least weeks prior to study treatment Brain metastases unless documented to be controlled post completion of local therapy (surgery and/or radiation therapy) for at least four weeks prior to registration history of arteriovenous malformations of the brain, history of brain infection (i.e., abscess, meningitis, or encephalitis), Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression; should participants develop brain metastases while on trial and have clinical benefit from GSK and GSK otherwise, participants may continue on drug after clinical management of the brain metastases with the permission of the principal investigator; GSK and GSK should be restarted between and weeks after the last radiation treatment Known brain metastasis; participants with brain metastasis can only be included if they were treated > week prior to enrollment with radiation and the effects of treatment have resolved; subjects with treated brain metastases must have a post-treatment brain magnetic resonance imaging (MRI) showing no further progression of prior lesions and no new metastatic lesions; subjects will be ineligible if they have any ongoing symptoms from brain metastases or if there continues to be radiographic evidence of cerebral edema Patients must have radiographically-confirmed recurrent brain metastases from a solid tumor after WBRT Patients will be excluded if they have had prior radiation to the brain Patients will be excluded if they have had prior surgical resection of brain for other brain tumors Concurrent radiation therapy is not allowed with the exception of brain metastases developing on study treatment Patients with active brain metastases. Patients with prior history of brain metastasis who have undergone local therapy (i.e. metastatectomy and/or radiation) and show no evidence of local recurrence or progression over the past months are eligible Patients receiving whole brain radiation within days prior to the first dose of study drugs will be excluded; NOTE: patients receiving palliative radiation (other than whole brain) before or during treatment may still be eligible as long as there are evaluable lesions that are not being irradiated Subjects with known central nervous system (CNS) metastases must have received whole-brain radiation or other appropriate therapy not less than weeks prior to starting the study drug, and exhibit clinical stability of brain disease as judged by the treating physician Any unresected lesions must measure < . cm in maximal extent on the contrasted MRI or CT brain scan obtained =< days prior to pre-registration; the unresected lesions will be treated with SRS; Note: the metastases size restriction does not apply to the resected brain metastasis; with resected brain metastases only surgical cavity size determines eligibility Has no evidence of new or enlarging brain metastases confirmed by post-treatment repeat brain imaging performed ? weeks after pre-treatment brain imaging, and Participants with central nervous system (CNS) metastases are not eligible, unless they have completed local therapy (eg, whole brain radiation therapy (WBRT), surgery or radiosurgery) and have discontinued the use of corticosteroids for this indication for at least weeks before starting treatment in this study. Any signs (eg, radiologic) or symptoms of brain metastases must be stable for at least weeks before starting study treatment Known intra-cerebral disease or brain mets Known brain metastases, uncontrolled seizure disorders, encephalitis, or multiple sclerosis Has brain metastases with evolving neurologic symptoms or a steroid requirement. Patients with treated brain metastases (received definitive radiation and/or underwent surgical resection) are eligible for therapy on this protocol; patients with clinical evidence of active brain metastases are ineligible for therapy on this protocol Subjects with asymptomatic brain metastases found on screening MRI may be entered into Phase b or into Group of the Phase a without prior radiation therapy to the brain. Subjects with minimally symptomatic brain metastases found on screening MRI may be entered into Phase b or into Group of the Phase a without prior radiation therapy to the brain if they do not require immediate surgical or radiation therapy Deep brain stimulator No history of prior whole brain radiation Any history of intracerebral arteriovenous malformation, cerebral aneurysm, brain metastases or stroke. Brain metastases that are:\r\n* Progressive or\r\n* Have required any type of therapy (including radiation, surgery or steroids) to control symptoms from brain metastases within days prior to the first study treatment Known brain metastases (systematic screening of patients not mandatory) Patients with known brain metastases are excluded unless they have had definitive treatment (e.g. whole brain radiotherapy or surgery or stereotactic radiation) for brain metastases with evidence of stable/improved disease on repeat imaging following definitive treatment The subject has uncontrolled metastases to the central nervous system (CNS). Subjects with brain metastases are eligible provided they have shown clinical and radiographic stable disease for at least days after definitive therapy and have not received prior whole brain radiation (Phase only). Participants with primary brain tumors or disease metastatic to the brain. There are no exclusion criteria except for individuals without a brain tumor and the location of the craniotomy; if the exposed area of brain is not compatible with peripheral stimuli or volitional activity the subject cannot be enrolled Histologically confirmed initial diagnosis of primary WHO Grade IV malignant glioma (glioblastoma), now recurrent; or Cohorts and 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 . Previous brain radiotherapy (SRS or whole brain radiation therapy [WBRT]) They have received standard anti-tumor treatment for their brain metastases without encephalopathy; No conditions that may compromise blood-brain barrier permeability (e.g., multiple sclerosis, recent brain trauma, Alzheimers 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 days prior to registration\r\n* Patients having received stereotactic radiation will be eligible if the radiation was completed at least days prior to registration\r\n* Patients having undergone surgical resection of brain metastases will be eligible after they have healed and recovered from the surgical intervention sufficiently to start systemic treatment for NSCLC, as determined by a neurosurgeon\r\n* No known leptomeningeal carcinomatosis Patients who present with symptomatic brain radionecrosis after they have received radiosurgery for brain metastases from primary solid tumor including but not limited to lung, breast, colorectal cancer but excluding melanoma, choriocarcinoma, renal cell carcinoma or gliomas Patient has a condition that may have affected the permeability of the blood-brain barrier (e.g., known brain metastases, meningeal metastases, brain injury, multiple sclerosis, recent brain injury, uncontrolled epilepsy) Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms; participants with previously diagnosed brain metastases are eligible if they have completed treatment at least weeks prior to registration, are neurologically stable and absence of new neurologic symptoms for the last 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 >= weeks before the first study drug; treatment for brain metastases may have included whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating physician Subject has known active brain or leptomeningeal metastases. Subjects with prior history of brain metastasis who have undergone local therapy (i.e. metastatectomy and/or radiation) and show no evidence of local recurrence or progression over the past months prior to screening are eligible. Patients with either a malignant central nervous system (CNS)-primary cancer or with brain metastases; patients do not need to undergo brain imaging unless indicated per standard workup and management (e.g. advanced stage lung cancer receiving definitive therapy) Primary brain cancer (presumed gliomas with no radiographic or clinical evidence of metastatic disease to the brain) SUBJECT: Must be at least year post completion of radiation therapy to the brain or brain and spine. Patients 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 dose History of epilepsy, brain damage, use of anticonvulsants for seizure prevention, concurrently using ketamine, symptomatic brain metastases Patient must not have brain metastases present prior to initiation of initial therapy or PCI Metastatic cancer to the brain for which palliative whole brain radiotherapy is recommended. Whole-brain radiation ? weeks Brain metastases requiring focal or whole brain radiation will be excluded Prior 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 (> month) of non-CNS malignancy in remission, without evidence of current/ prior brain metastasis, will also not disqualify patient from participating. Prior brain cancer Prior whole brain radiation History of radiation therapy to the brain Patients with a diagnosis of intra-axial brain tumor at initial diagnosis or patients with known treated brain tumors on follow-up with concern for imaging progression Any indication of a risk for an imminent brain herniation, as evaluated by the Principal Investigator, based on the findings on brain MRI. Treatment with whole brain radiation therapy (WBRT) within months prior to screening. Patient must meet at least one of the four following criteria regarding brain tumor diagnosis:\r\n* Histological diagnosis of a brain tumor\r\n* Histological diagnosis of systemic cancer and brain MR imaging suggestive of metastatic disease to the brain\r\n* Pre-operative brain MR imaging suggestive of a brain tumor\r\n* Radiographic diagnosis of brain tumor in an inoperable location (e.g., brainstem) Patient must be clinically eligible for and elect to be treated with GK alone without whole-brain radiation therapy (WBRT) Patients must have been diagnosed with one of the following:\r\n* Primary brain tumor (glioma, glioblastoma [GBM] etc); or\r\n* Up to brain metastases Patients must be scheduled to undergo standard brain cancer interventions:\r\n* Chemotherapy or targeted antiangiogenic therapy, in the case of primary brain tumor; or\r\n* Stereotaxic radiotherapy (SRS) or whole brain radiotherapy (WBRT), in the case of brain metastases Patients with cancer that spread to the brain Patients with brain metastases may participate if they have undergone appropriate treatment for the lesion(s), are at least two weeks post treatment without evidence for post-treatment progression, have no significant neurologic symptoms, and no longer require steroids for the reason of brain metastases Patients with 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.