Patients with untreated brain metastases, spinal cord compression, or leptomeningeal carcinomatosis should be excluded from this clinical trial; patients whose brain metastases have been treated may participate provided they show radiographic stability (defined as 2 brain images, both of which are obtained after treatment to the brain metastases; these imaging scans should both be obtained at least four weeks apart and show no evidence of intracranial progression); in addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on a steroid dose of =< 10 mg/day of prednisone or its equivalent (and anti-convulsants) for at least 14 days prior to the start of treatment
Inclusion Criteria\n\n        Histologically confirmed HER2+ breast carcinoma, with HER2+ defined by in situ\n        hybridization (ISH) or fluorescence in situ hybridization (FISH) methodology\n\n        Received previous treatment with trastuzumab, pertuzumab, and T-DM1\n\n        Progression of unresectable locally advanced or metastatic breast cancer after last\n        systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy\n\n        Have measurable or non-measurable disease assessable by RECIST 1.1\n\n        At least 18 years of age at time of consent\n\n        Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1\n\n        Adequate hepatic and renal function\n\n        Left ventricular ejection fraction (LVEF) ? 50%\n\n        CNS Inclusion - Based on screening brain magnetic resonance imaging (MRI), patients must\n        have one of the following:\n\n          -  No evidence of brain metastases\n\n          -  Untreated brain metastases not needing immediate local therapy\n\n          -  Previously treated brain metastases not needing immediate local therapy\n\n               1. Brain metastases previously treated with local therapy may either be stable since\n                  treatment or may have progressed since prior local CNS therapy\n\n               2. Patients treated with CNS local therapy for newly identified lesions found on\n                  contrast brain MRI performed during screening for this study may be eligible to\n                  enroll if the following criteria are met:\n\n             i. Time since whole brain radiation therapy (WBRT) is ? 21 days prior to first dose of\n             study treatment, time since stereotactic radiosurgery (SRS) is ? 7 days prior to first\n             dose of study treatment, or time since surgical resection is ? 28 days.\n\n        ii. Other sites of evaluable disease are present\n\n        c. Relevant records of any CNS treatment must be available to allow for classification of\n        target and non-target lesions\n\n        Exclusion Criteria\n\n        Previously been treated with:\n\n          1. lapatinib within 12 months of starting study treatment (except in cases where\n             lapatinib was given for ? 21 days and was discontinued for reasons other than disease\n             progression or toxicity)\n\n          2. neratinib, afatinib, or other investigational HER2/epidermal growth factor receptor\n             (EGFR) tyrosine kinase inhibitor (TKI) at any time previously\n\n          3. previously been treated with capecitabine for metastatic disease except in cases where\n             capecitabine was given for < 21 days and was discontinued for reasons other than\n             disease progression or toxicity. Patients who have received capecitabine for adjuvant\n             or neoadjuvant treatment at least 12 months prior to starting study treatment are\n             eligible.\n\n        Clinically significant cardiopulmonary disease\n\n        Carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease\n\n        Positive for human immunodeficiency virus (HIV)\n\n        Unable for any reason to undergo MRI of the brain\n\n        CNS Exclusion - Based on screening brain MRI, patients must not have any of the following:\n\n        Any untreated brain lesions > 2.0 cm in size, unless discussed with medical monitor\n\n        Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a\n        total daily dose of > 2 mg of dexamethasone (or equivalent)\n\n        Any brain lesion thought to require immediate local therapy. Patients who undergo local\n        treatment for such lesions identified by screening contrast brain MRI may still be eligible\n        for the study based on criteria described under CNS inclusion criteria\n\n        Known or concurrent leptomeningeal disease (LMD)\n\n        Poorly controlled seizures
Have known symptomatic brain metastases requiring steroids. Subjects with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and have radiographically stable disease for at least 3 months prior to study entry. Note: up to 10 mg per day of prednisone equivalent will be allowed.
Patients with known brain metastases must either meet the additional criteria and enroll as part of the Progressive Brain Metastases Cohort, or have clinically controlled neurologic symptoms, defined as surgical excision and/or radiation therapy followed by 14 days of stable neurologic function prior to registration; patients with previously incidentally discovered or asymptomatic brain metastasis(es) must receive surgical excision and/or radiation therapy prior to registration; patients with progressive brain metastases following prior treatment are not eligible for the Standard Cohort, but may be considered for the Progressive Brain Metastases Cohort
Patients must not have brain metastases unless brain metastases have been treated and patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration
Patients with a history of treated brain metastases who are asymptomatic and have not received steroid therapy in the 14 days prior to registration are eligible; anti-seizure medications are allowed provided they are non-enzyme inducing (e.g. topiramate, levetiracetam, gabapentin)
Patients with known brain metastases must have baseline brain imaging within 4 weeks prior to study registration and meet all of the following criteria:\r\n* Have completed treatment to all symptomatic brain metastases (with whole brain radiation or radiosurgery) >= 4 weeks prior to registration, or have undergone complete neurosurgical resection >= 3 months prior to registration\r\n* Be clinically stable from brain metastases at time of screening, if no treatment was administered\r\n* Known leptomeningeal disease is not allowed
Participants may not have clinically symptomatic brain metastases or leptomeningeal disease; patients may be on a stable dose of corticosteroids to control brain metastases if they have been on a stable dose for two weeks (14 days) prior to study treatment and are clinically asymptomatic
Patients must not have known brain metastases unless brain metastases have been treated and patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 14 days prior to registration
Participants with known brain metastases will be eligible if they have completed the primary brain therapy (such as whole brain radiotherapy, stereotactic radiosurgery or complete surgical resection) and if they have remained clinically stable, asymptomatic and off of steroids for at least 28 days before starting study treatment.
Participants with symptomatic uncontrolled brain metastases; baseline brain imaging by CT or MRI is required for all patients; participants with brain metastases that have been treated with prior radiation therapy and are stable on a subsequent scan are allowed; participants with untreated possible brain metastases that are new at the time of screening and are < 1 cm and asymptomatic are allowed; the participant can receive corticosteroids as long as these were started and at a stable dose at least 28 days prior to treatment
Patients with brain metastases treated with whole brain radiation that have been stable for 2 months are eligible; patients with brain metastases treated with gamma knife or surgery are allowed to participate after 3 weeks have elapsed since their procedure; demonstration of brain stability by an imaging study after the procedure is required for gamma knife or central nervous system (CNS) surgery patients; subjects are excluded if they have leptomeningeal or metastases causing spinal cord compression that are symptomatic or untreated or not stable for >= 3 months (must be documented by imaging) or requiring corticosteroids; subjects on a stable dose of corticosteroids > 1 month or who have been off of corticosteroids for at least 1 week can be enrolled with approval of the medical monitor
Known brain metastases (unless previously treated and well controlled for a period of at least 3 months).
Symptomatic or unstable brain metastases; (Note: Asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days prior to randomization are eligible to participate in the study)
Known symptomatic brain metastases (NOTE: patients with treated epidural disease are allowed)
16. Symptomatic or untreated central nervous system metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation, and/or corticosteroids. Subjects with previously treated brain metastases may participate provided they are clinically stable for at least 8 weeks prior to study entry, have no evidence of new or enlarging metastases, and are off steroids;
Known central nervous system, meningeal, or epidural disease. However, subjects with known brain metastases are allowed if the brain metastases are stable for ?4 weeks before the first dose of study treatment.
Asymptomatic 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)
CNS malignancy, the known presence of untreated or symptomatic CNS metastases. Subjects with treated brain metastasis must be stable and off steroids and anti-convulsants for at least 1 month prior to the start of study treatment. Subjects with suspected brain metastases at Screening should have a CT/MRI of the brain prior to study entry.
Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms; participants with previously diagnosed brain metastases are eligible if they have completed treatment at least one month prior to trial therapy initiation, are neurologically stable with an absence of new neurological symptoms for at least 4 weeks prior to study entry, and have recovered from effects of radiotherapy or surgery; any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 2 weeks before the first study drug; treatment for brain metastases may include whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating physician
Participants with CNS metastases are not eligible, unless they have completed local therapy (eg, whole brain radiation therapy [WBRT], surgery or radiosurgery) and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs (eg, radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment
Participants with untreated brain metastases. Participants with treated metastases that are clinically stable and asymptomatic for at least 2 weeks and who are off or receiving low-dose corticosteroid treatment (=<10 mg prednisone or equivalent) for at least 2 weeks prior to study treatment are eligible
Stable brain metastases allowed (> 2 weeks, clinically-stable post treatment with surgery +/- radiation or radiation alone and off steroids)
Patients with known brain metastases should be excluded from this clinical trial; however, patients with previously treated and stable brain metastases are eligible as long as they are no longer requiring steroids, completed radiation therapy more than 2 weeks prior to the first dose of study regimen and have no seizures or worsening neurologic symptoms
If there is a known history of brain metastases, either treated with radiation therapy or untreated, the metastatic disease must be stable in the judgment of the Principal Investigator and must not require ongoing treatment with corticosteroids or anticonvulsants.
Brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery and stable for at least 3 months before planned first dose of study drug
Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before the first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the start of study treatment
Participants 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 weeks
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
Subjects with previously treated brain metastases may participate provided they are not using escalating steroids for brain metastases at the time of trial consent and study drug initiation, and there remains a measurable lesion in the CNS
Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms; participants with previously diagnosed brain metastases are eligible if they have completed treatment at least 2 weeks prior to trial therapy initiation, are neurologically stable, and have recovered from the acute effects of radiotherapy or surgery; any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 2 weeks before the initiating protocol therapy; treatment for brain metastases may include surgery, whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating physician
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
Symptomatic brain metastases; stable and treated central nervous system (CNS) disease allowed; patients with treated, asymptomatic brain metastases are eligible if there has been no change in brain disease status for at least two (2) weeks prior to initiating study treatment; anticonvulsant therapy will be allowed if patient is on a stable or decreasing dose of anticonvulsant treatment for at least two (2) weeks prior to initiating study treatment
Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms; participants with previously diagnosed brain metastases are eligible if they have:\r\n* Completed treatment (whole brain radiotherapy, radiosurgery, or a combination) at least 3 months prior to trial therapy initiation,\r\n* Are neurologically stable, and\r\n* Have recovered from effects of radiotherapy or surgery\r\n* Any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 2 weeks before prior to registration
Patients with brain metastases which are symptomatic may not be enrolled; those subjects with untreated brain metastases =< 1 cm may who are asymptomatic and for whom there are no plans for surgery, radiation or corticosteroid use may be considered eligible at the discretion of the principal investigator; subjects with brain metastases that have been treated and are stable for at least 1 month are eligible if they are asymptomatic and not receiving corticosteroids
Uncontrolled brain metastases (Stable brain metastases either treated or being treated with a stable dose of anticonvulsants, with no dose change within 28 days before enrollment, will be allowed.).
Patient with untreated or inadequate controlled brain metastases. Brain metastases or lymphoma with CNS involvement previously treated by radiotherapy or other modality and stable for at least 3 months prior to screening without requirement of corticosteroids or anticonvulsants are permitted
Untreated brain metastases (pts with treated brain mets who are off steroids and anticonvulsants and stable for at least 1 month at the time of Screening are eligible)
Largest brain metastases volume measures less than 14.15 cc^3
If they have brain metastases located in the brain stem (including midbrain, pons, or medulla)
Patients with leptomeningeal disease are not eligible but patients with brain metastases are eligible – these patients should commence treatment on study > 1 week after completion of gamma knife or whole brain radiotherapy or > 4 weeks after surgical resection of brain metastasis; patients should ideally be off steroids at the start of study treatment, however patients on steroid taper and a dose of no more than 2 mg/day of dexamethasone can begin study treatment; and steroids should be tapered off as quickly as clinically feasible; repeat brain magnetic resonance imaging (MRI) after radiation is not required for eligibility but is strongly recommended, to establish the pre-treatment baseline status of any brain metastases, necessary to accurately assess for response or progression; patients with untreated, asymptomatic brain metastasis not requiring steroids are also eligible, however, these patients need to be discussed with the study PI prior to being registered
Patients with uncontrolled brain metastases. Existing brain metastases must have been previously treated and currently stable.
Patients must have between 1 to 5 new or recurrent lesions suspicious for metastatic RCC on diagnostic imaging\r\n* Each extracranial lesion must be =< 6 cm and amenable to SBRT or surgical excision\r\n* Patients must have 3 or fewer brain metastases, of size =< 4 cm\r\n** Brain metastases must be treated prior to enrollment in the study; the modality of treatment of brain metastases can include surgical resection, whole brain radiotherapy, stereotactic radiosurgery, or any combination of the above
Patients with active brain or subdural metastases are not eligible, unless they have completed local (radiation) therapy and have discontinued the use of corticosteroids or have been on stable dose of corticosteroids for at least 4 weeks before starting study treatment; any symptoms attributed to brain metastases will be stable for at least 4 weeks before starting study treatment
Patients with known untreated brain metastases; patients with known, treated brain metastases must be stable with no symptoms for four weeks after completion of that treatment, with image documentation required, and must either be off steroids or on a stable dose of steroids for at least two weeks prior to protocol enrollment; patients with known leptomeningeal metastases are excluded, even if adequately treated; patients without known brain metastases do not require radiologic imaging prior to enrollment
Brain metastases (symptomatic or nonsymptomatic) that have not been treated previously, are progressive, or require any type of therapy (e.g., radiation, surgery, or steroids) to control symptoms from brain metastases within 30 days prior to first study treatment dose Cobimetinib-Specific Exclusion Criteria
Presence of active brain metastases or epidural disease\r\n* Subjects with brain metastases are eligible if previously treated with whole brain radiation or radiosurgery, and do not require steroid treatment for at least 2 weeks before starting study treatment\r\n* Subjects with epidural disease are eligible if previously treated with radiation or surgery, are asymptomatic, and do not require steroid treatment for at least 2 weeks before starting study treatment
Patients 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.
Known metastases in the brain or active epidural disease (NOTE: patients with treated epidural disease are allowed)
Patients with active brain metastases are not eligible; patients with brain metastases that have been treated and stable for > 30 days following treatment will be eligible
Patients can have concomitant brain metastases as long as they do not require active treatment or have been treated
Patients with known brain metastases are not excluded from this clinical trial. Patients who received palliative radiation (for brain metastases) are eligible if they have been asymptomatic for at least 4 weeks without use of maintenance steroid therapy, and last received radiation at least 4 weeks prior to proposed start of therapy
All subjects with brain metastases, except those meeting the following criteria:\r\n* Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment\r\n* No history of intracranial or spinal cord hemorrhage\r\n* No evidence of interim central nervous system (CNS) disease progression\r\n* Metastasis to the midbrain, pons, and medulla\r\n* No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable.\r\n* Subjects must be either off steroids or on a stable or decreasing dose of =< 10 mg daily prednisone (or equivalent).
Subjects with symptomatic brain metastases will be excluded from trial secondary to poor prognosis. However, subjects who have asymptomatic brain metastases, and those had treatment for their brain metastasis and whose brain disease is stable without steroid therapy for 2 weeks may be enrolled (replacement doses =< 10 mg of prednisone or equivalent per day are allowed)
Subjects with untreated or uncontrolled brain metastases. Patients with asymptomatic brain metastases or previously treated brain metastases that are stable (i.e. not requiring corticosteroids) at the time of study start will be eligible
Patients with untreated or uncontrolled brain metastases or evidence of leptomeningeal disease. Patients with asymptomatic brain metastases or previously treated brain metastases that are stable (i.e. not requiring corticosteroids) at the time of study start will be eligible
Untreated symptomatic brain metastases (treated brain metastases are allowed provided > 14 days have elapsed from completion of radiotherapy and patient is neurologically stable as assessed by treating physician)
Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment
COHORT 1: HORMONE RECEPTOR POSITIVE BREAST CANCER: Patients with symptomatic brain metastases or leptomeningeal involvement; patients with asymptomatic or brain metastases that have been treated with radiation at least 4 weeks prior to first dose of study treatment are allowed
COHORT 2: TRIPLE NEGATIVE BREAST CANCER: Patients with symptomatic brain metastases or leptomeningeal involvement; patients with asymptomatic or brain metastases that have been treated with radiation at least 4 weeks prior to first dose of study treatment are allowed
COHORT 3: ENDOMETRIAL CANCER: Patients with symptomatic brain metastases or leptomeningeal involvement; patients with asymptomatic or brain metastases that have been treated with radiation at least 4 weeks prior to first dose of study treatment are allowed
For patients with known and treated brain metastases is allowed in this study if they fulfill ALL of the following criteria:\r\n* The lesions have remained radiologically stable for at least six weeks after completion of brain irradiation or stereotactic brain radiosurgery, and must remain stable at the time of study entry\r\n* There is no mass effect present radiologically and no steroids requirement for symptom control for more than 4 weeks
Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before the first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the start of study treatment.
ARM I INCLUSION CRITERIA: If subjects have known brain metastases (mets) that were treated previously with local therapies, surgery, and/or radiation, these lesions must be stable for at least 30 days prior to enrollment
Patients with “treated and stable” brain lesions of a duration of > 4 weeks may be enrolled
Brain tumors and/or brain metastases unless they are asymptomatic, stable on recent imaging (not dated more than 30 days from the inclusion date), and have not required active treatment in the last 6 months
Patients with clinically symptomatic brain metastases or leptomeningeal disease; patients may be on a stable dose of corticosteroids to control brain metastases if they have been on a stable dose for two weeks prior to study treatment and are clinically asymptomatic
Patients with known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they are asymptomatic or have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable
Patients with controlled brain metastases are allowed on protocol if they had solitary brain metastases that was surgically resected or treated with radiosurgery or Gamma knife, without recurrence or edema for 1 month (4 weeks).
Has spinal cord compression or clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment (1 week for stereotactic radiotherapy).
Participants with brain or subdural metastases are not eligible unless the metastases are asymptomatic and do not require treatment or have been adequately treated by local therapy and have discontinued the use of corticosteroids for this indication for at least 28 days prior to study drug administration.
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 untreated symptomatic brain metastases; patients with treated brain metastases will be allowed if brain imaging obtained greater than 7 days from trial enrollment reveals stable disease; patients with small (< 3 mm) asymptomatic brain metastasis are allowed to enroll; patients on steroids doses higher than 10 mg of prednisone (or its equivalent) are excluded
The total number of tumors requiring SRT must be =< 5\r\n* Note: Regardless of the number of brain metastases that will be treated with SRT, the brain metastases will be considered to be one tumor
Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before the first dose of study treatment; eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the start of study treatment
Patients with clinically active brain metastases. However, patients with previously currently stable brain metastases on medication (i.e., steroids and/or anti-seizure medications) may be enrolled after consultation with the Medical Monitor.
Patients with previously untreated brain metastases should be excluded; patients with treated and stable (> 4 weeks) brain metastases may be eligible for enrollment
All subjects with brain metastases, except those meeting the following criteria:\r\n* Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment\r\n* No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable)\r\n* Subjects must be either off steroids or on a stable or decreasing dose of =< 10 mg daily prednisone (or equivalent)
Participants with symptomatic brain metastases will be excluded from this clinical trial; subjects with asymptomatic, stable brain metastases and subjects who, if they have been previously treated for these conditions that are asymptomatic in the absence of corticosteroid therapy are allowed to enroll; brain metastasis must be stable with verification by imaging (brain magnetic resonance imaging [MRI] completed at screening demonstrating no current evidence of progressive brain metastases); if asymptomatic brain metastasis are first identified on the required pre-study scans, another set of scans must be completed to confirm that they are stable
Documented brain metastases that are untreated, symptomatic, or require therapy to control symptoms; participants with previously diagnosed brain metastases are eligible if they have completed treatment at least one month prior to trial registration, are neurologically stable, and have recovered from effects of radiotherapy or surgery\r\n* Any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 2 weeks before the first study drug\r\n* Treatment for brain metastases may have included whole brain radiotherapy, radiosurgery, or a combination as was deemed appropriate by the treating physician\r\n* Patients who meet the above criteria and are clinically stable on anticonvulsant medication are eligible only if their anti-convulsant does not alter hepatic cytochrome P450 activity in a way that might interfere with metabolism of abemaciclib
Subjects with radiographically stable treated brain metastases are eligible but must not have been on steroid therapy for at least 4 weeks
Brain metastases unless previously treated and well controlled for at least 3 months
Uncontrolled brain metastases; patients treated with radiation >= 4 weeks prior with follow up imaging showing control are eligible
Previously treated (surgery and/or radiation therapy) or untreated brain metastases are eligible, provided that patients are asymptomatic and not requiring escalating doses of corticosteroids
Patients with known symptomatic brain metastases requiring systemic corticosteroids; patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable; mild neurological deficit is allowed, if it does not interfere with the ability to judge the safety on the trial
Treated stable brain metastases are allowed, as long as patient does not require steroids or anti-seizure medications
Patients with treated, stable, and asymptomatic brain metastases are eligible
Participants with history of brain metastases who have not shown clinical and radiographic stable disease for at least 28 days after definitive therapy.
All subjects with brain metastases, except those meeting the following criteria:\r\n* Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment \r\n* No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable)\r\n* Subjects must be either off steroids or on a stable or decreasing dose of =< 10 mg daily prednisone (or equivalent)
Patients with clinically symptomatic brain metastases or who required treatment for brain metastases within 4 weeks of registration (stable sequelae acceptable if treatment has been completed; these lesions cannot be used as target lesions)
Brain metastases are allowed, as long as they are stable and do not require treatment with anticonvulsants or escalating doses of steroids
All subjects with brain metastases, except those meeting the following criteria:\r\n* Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment \r\n* No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable)\r\n* Subjects must be either off steroids or on a stable or decreasing dose of < 10 mg daily prednisone (or equivalent)
No known or suspected brain metastases (NOTE: patients with treated epidural disease are allowed)
Has untreated brain metastasis. In the case of a solitary brain metastasis which has been resected, there must be evidence of a disease-free interval of at least 3 months post-surgery. For brain metastases treated with whole brain or stereotactic radiation therapy, brain imaging must be stable > 3 months. All subjects previously treated for brain metastases must be stable off corticosteroid therapy for at least 28 days prior to C1D1.
Patients with 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)
Clinical stability of brain metastases for at least 4 weeks prior to first day of study therapy.
All subjects with brain metastases, except those meeting the following criteria: \r\n* Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment\r\n* No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable)\r\n* Subjects must be either off steroids or on a stable or decreasing dose of =< 10 mg daily prednisone (or equivalent)
Patients with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids, anti-convulsants or have been on stable dose of corticosteroids for at least 4 weeks before starting study treatment; any symptoms attributed to brain metastases must be stable for at least 4 weeks before starting study treatment
Patients with previously treated (with radiation or surgery) brain metastases that are stable are allowed; patients with stable or progressing metastases must have metastases =< 1.5 cm, be asymptomatic, and either not be on steroids or be on 10 mg prednisone equivalent or less
Symptomatic or unstable brain metastases; (Note: asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroid for treatment of brain metastases for at least 14 days [or decreasing dose of corticosteroid] are eligible to participate in the study); patients with primary central nervous system tumors are eligible
Previously treated brain metastases (surgery and/or radiation therapy) are eligible, provided that patients are asymptomatic and not requiring corticosteroids
Active 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)
Patients with symptomatic uncontrolled brain metastases are excluded; (patients with stable treated or asymptomatic untreated brain metastasis not requiring glucocorticoids are allowed)
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
PHASE I: Patients with treated brain metastases (surgery, whole or stereotactic brain radiation) are allowed provided the lesions have been stable for at least 2 weeks and the patient is off steroids or is on a stable dose of steroids; patients with brain metastases should not require use of enzyme-inducing antiepileptic drugs (e.g., carbamazepine, phenytoin, or phenobarbital) within 14 days before first dose and during study; use of newer antiepileptics that do not produce enzyme induction drug-drug interactions (DDIs) is allowed
PHASE II SCLC: Patients with treated brain metastases (surgery, whole or stereotactic brain radiation) are allowed provided the lesions have been stable for at least 2 weeks and the patient is off steroids or is on a stable dose of steroids; patients with brain metastases should not require use of enzyme-inducing antiepileptic drugs (e.g., carbamazepine, phenytoin, or phenobarbital) within 14 days before first dose and during study; use of newer antiepileptics that do not produce enzyme induction drug-drug interactions (DDIs) is allowed
Patients with brain metastases involving the brainstem or chiasm
Patients with treated and clinically stable brain metastases are allowed
Subjects with untreated or uncontrolled brain metastases or evidence of leptomeningeal disease; patients with asymptomatic brain metastases or previously treated brain metastases that are stable (i.e. not requiring corticosteroids) at the time of study start will be eligible
Active uncontrolled or symptomatic brain metastases; previously treated and clinically stable, as per investigator’s judgment, brain metastases are permitted
Brain metastases unless previously treated and well controlled for at least 3 months
Clinically active brain metastases; radiological documentation of absence of active brain metastases at screening is required for all patients; prior evidence of brain metastasis successfully treated with surgery or radiation therapy will not be exclusion for participation as long as they are deemed under control at the time of study enrollment
The subject has active brain metastases or epidural disease
All brain metastases must be outside the brain stem (midbrain, pons and medulla)
Symptomatic or unstable brain metastases; (Note: asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days prior to registration are eligible to participate in the study)
CERITINIB 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 administration
REGORAFENIB EXCLUSION CRITERIA: Known symptomatic brain metastases leptomeningeal involvement on unstable/increasing doses of steroid\r\n* Patients with asymptomatic brain metastases or leptomeningeal carcinomatosis may be enrolled at the discretion of the Sponsor as long as the patient is in clinically stable condition and, if requiring steroid, must be on a stable or decreasing dose for at least 5 days prior to regorafenib administration
Patients may have parenchymal brain metastases if stable (no evidence of progression) for at least 1 month after local therapy (radiation or surgery); leptomeningeal disease is excluded; must have completed any prescribed steroid taper prior to registration
Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 2 weeks before the first dose of study treatment; eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the start of study treatment
Known or suspected untreated brain metastases; patients with radiographically stable, asymptomatic previously irradiated lesions are eligible provided patient is >= 4weeks beyond completion of cranial irradiation and >= 3 weeks off of corticosteroid therapy at the time of study intervention
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nCNS disease: subjects with symptomatic brain metastases will be excluded from trial secondary to poor prognosis; however, subjects who have had treatment for their brain metastasis and whose brain disease is stable without steroid therapy for 4 weeks may be enrolled; baseline imaging to rule out brain metastases is not required for screening, but should be performed prior to study enrollment if clinically indicated
Patients may have treated and stable brain metastases; they must be off steroids and must have had stable brain metastases for at least 6 months
Meningeal metastases or brain metastases that are symptomatic or untreated\r\n* Note: patients who are asymptomatic and have had post-treatment imaging that indicates stable brain disease are eligible; (patients with meningeal metastasis are not eligible even if stable following treatment); also, note that brain imaging is required within 8 weeks prior to initiation of study therapy
Brain metastases or bone metastases; patients with brain metastases must have received treatment for them (resection or stereotactic radiosurgery [SRS]) and these metastatic foci must be stable for 8 weeks prior to starting study drug
Previously treated patients with non-squamous NSCLC who have had brain metastases at any point in their treatment history are eligible for enrollment on this clinical trial; (patients must have received at least one regimen for systemic disease which may be cytotoxic or oral tyrosine kinase inhibitor therapy)\r\n* Patients with clinically asymptomatic (no requirement for systemic corticosteroids) untreated brain metastases will be allowed on trial at the discretion of the treating physician\r\n* Patients who have undergone treatment for their brain metastases with whole brain radiotherapy, stereotactic radiosurgery, or surgical resection must be clinically stable and recovered from all procedures at the time of study enrollment
Patients with locally treated, stable, and/or asymptomatic brain metastases are eligible
Patients may be enrolled with a history of treated brain metastases that are clinically stable for >= 4 weeks prior to start of study treatment
The subject has active brain metastases or epidural disease who have not been treated with radiation therapy (Note: subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 2 months before starting study treatment; (baseline brain imaging with contrast-enhanced CT or MRI scans for subjects with known brain metastases is required to confirm eligibility)
Patients with brain metastases may participate in this clinical study provided that symptoms have been controlled with standard therapies and/or appropriate medications; the principal investigator (P.I.) will carefully evaluate the suitability of patient participation when brain metastases are present
Untreated, symptomatic, or progressive brain metastases; participants must have no radiographic or other signs of progression in the brain for >= 1 month after completion of local therapy; any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 4 weeks prior to first study treatment
Clinically active brain metastases; radiological documentation of absence of active brain metastases at screening is required for all patients; prior evidence of brain metastasis successfully treated with surgery or radiation therapy will not be exclusion for participation as long as they are deemed under control at the time of study enrollment
Known brain metastases, unless previously treated and asymptomatic for 3 months and not progressive in size or number for 3 months
No more than 1 Brain Met can be treated under this protocol
Known uncontrolled brain, leptomeningeal or epidural metastases (unless treated and well controlled for at least 4 weeks prior to Cycle 1 Day 1). Controlled brain metastases that require continuous high dose corticosteroid use within 4 weeks of Day
Patients with prior history of treated brain metastases who are off steroids and have stable metastatic brain disease for at least 3 months are eligible
Patients with rapidly advancing parenchymal brain metastases (Cohort D)
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
Symptomatic brain metastases; asymptomatic brain metastases are allowed provided that they have been treated, have been stable for greater than (>) 6 weeks as documented by radiographic imaging, and do not require prolonged (>14 days) systemic corticosteroid therapy
Have symptomatic central nervous system metastases. Patients with brain metastases that have been previously treated and are stable for ? 4 weeks or treated with gamma knife surgery and are stable for ? 2 weeks are allowed to enter the study.
Uncontrolled brain metastases or treatment by neurosurgical resection or brain biopsy within 4 weeks prior to Day 1.
Brain metastases, which are symptomatic; patients with treated, brain metastases are eligible with stable brain disease for at least 4 weeks without the requirement for steroids or anti epileptic therapy
Patients with asymptomatic brain metastases that have been treated are eligible if the following criteria are met: No history of seizures in the preceding 6 months. Definitive treatment must have been completed >/= 4 weeks prior to registration. Subjects must be off steroids that were being administered because of brain metastases or related symptoms for >/= 2 weeks. Post-treatment imaging within 2 weeks of registration must demonstrate stability or regression of the brain metastases.
Known brain metastases (unless previously treated and well controlled for a period of > or = 3 months).
Presence of brain metastases, unless the patient received brain irradiation, including adequate stereotactic radiosurgery, at least 4 weeks prior to randomization, and is stable, asymptomatic, and off steroids for at least 3 weeks prior to randomization
Patients with known brain metastases may be included in the study, providing they are clinically stable.
Patients with untreated, symptomatic brain metastases should be excluded from this clinical trial (patients with asymptomatic brain metastases amenable to treatment with Gamma Knife radiosurgery [“GKRS”] are eligible and may receive GKRS while on protocol)
Symptomatic central nervous system metastases; subjects with brain metastases that have been previously treated and are stable for 4 weeks off steroids are allowed; patients must be stable off steroids for brain metastases for at least 7 days; subjects with asymptomatic clinically insignificant brain metastases not requiring treatment are allowed; the exception does not include carcinomatosus meningitis which is excluded regardless of clinical stability
Has untreated CNS metastases and/or carcinomatous meningitis that meets RECIST criteria identified either on the baseline brain imaging obtained during the screening period or identified prior to signing the informed consent form (ICF); patients whose brain metastases have been treated may participate provided they show radiographic stability (defined as 2 brain images, both of which are obtained after treatment to the brain metastases; these imaging scans should both be obtained at least four weeks apart and show no evidence of intracranial progression). In addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on a steroid dose of =< 10mg/day of prednisone or its equivalent and not requiring anticonvulsants for at least 14 days prior to the start of treatment
RENAL COHORT: Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 2 weeks before the first dose of study treatment; eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the start of study treatment
Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before the first dose of study treatment; eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the start of study treatment
Brain metastases considered unstable as: a. without confirmed stability over 60 days in patients previously treated with prior surgery or radiation; OR b. associated with symptoms and/or findings; OR c. requiring corticosteroids or anticonvulsants in the prior 60 days.
Patients with treated brain metastases are eligible for study participation; patients may not receive ongoing treatment with steroids at screening; anticonvulsants (at stable dose) are allowed; treatment for brain metastases may be whole?brain radiotherapy, radiosurgery, neurosurgery, or a combination as deemed appropriate by the treating physician; radiotherapy and stereotactic radiosurgery must be completed at least 28 days prior to randomization
Patients with a history of resected brain metastases are eligible only if they are asymptomatic and have stable MRI scans for 3 consecutive months, including =< 28 days of study registration
Patients who receive stereotactic radiosurgery or whole brain radiation for brain metastases are eligible only if they are asymptomatic and have stable MRI scans for 3 consecutive months, including =< 28 days of study registration
Subjects with known symptomatic brain metastasis are not suitable for enrolment. Subjects with asymptomatic, stable, treated brain metastases are eligible for study entry.
Known brain metastases or CNS cancer unless adequately treated with radiotherapy and/or surgery and stable for ? 2 mo
Subjects with treated brain metastases are eligible provided the metastases are clinically stable and greater than 8 weeks has elapsed from time of treatment and date of initiation of study drug
Patients with brain metastases are allowed provided that:\r\n* No leptomeningeal disease is present\r\n* Intracranial disease is controlled by prior local therapies (craniotomy, stereotactic radiosurgery, whole brain irradiation), as evidenced by brain MRI 4 weeks post treatment indicating no new intracranial disease\r\n* Stable or decreasing dose of steroids provided patient on =< 20 mg of prednisone or its equivalent daily
Extensive active brain disease including symptomatic brain metastases or presence of leptomeningeal disease \r\n* NOTE: Patients with brain metastasis, after definitive therapy with surgery or stereotactic radiation and stable off steroids for >= 4 weeks, are eligible
Patients with stable and controlled brain metastases for at least 3 months who also do not require steroids
Patients with known brain metastases should be excluded from this clinical trial; previously treated brain metastases, neurologically stable, and no ongoing or anticipated need for steroid therapy are eligible
History 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 screening
Patients with brain metastases may participate in this trial provided they are clinically stable; patients who are < 1 month from definitive therapy, receiving steroid therapy or taper, or anti-convulsant medications (started for brain metastases) must not be included
Patients with treated, stable, and asymptomatic brain metastases are eligible
Extensive active brain disease, including symptomatic brain metastases or the presence of leptomeningeal disease\r\n* Patients with brain metastasis, after definitive therapy with surgery or stereotactic radiation and stable off steroids for > 4 weeks, are eligible
Study participants with brain metastases are excluded unless these have been definitively treated and are radiographically stable for at least 1 month; the study participant must also demonstrate a stable physical exam and must have discontinued systemic steroids for treatment of edema related to brain metastases or treatment for over 7 days
No active brain metastases or epidural disease; patients with brain metastases previously treated with whole brain radiation or radiosurgery or patients with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 12 weeks before starting study treatment; baseline brain imaging with contrast-enhanced CT or MRI scans for patients with known brain metastases is required to confirm eligibility
Patients who have had brain metastases will be eligible only if all of the following are true:\r\n* The total number of brain metastases ever is =< 3\r\n* All are less than or equal to 2 cm\r\n* They have been resected surgically or have been treated with gamma-knife or stereotactic radiosurgery\r\n* The patient has not taken any steroids =< 30 days prior to registration for the purpose of managing their brain metastases
Patients with known brain metastases may be enrolled if this site of disease has been adequately treated, the patient does not require steroids, and the patient has been stable for at least 3 months prior to enrollment
Patients with a history of brain metastases are eligible if they have been treated with radiation and have stable brain metastases at least 3 months after radiation and must also be off steroids
Patients with brain lesions that have been treated with whole brain radiotherapy and are clinically stable for at least 4 weeks, are not taking steroids and are not receiving enzyme-inducing anticonvulsants will be eligible
Patients with resected or radiated brain metastases or those treated with stereotactic radiation therapy are eligible, provided they have been off steroids for at least 2 weeks; no history of stroke within the past 6 months
Evidence of active brain metastases, including leptomeningeal involvement (prior evidence of brain metastasis are permitted only if treated and stable and off therapy for ? 4 weeks prior to first dose of study drug).
Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery and stable for at least 3 months before randomization.
DISEASE 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 registration
Known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, have discontinued corticosteroid treatment for these metastases for at least 4 weeks prior to study entry and are neurologically stable.
Known brain metastases, unless stable or previously treated.
Participants with known brain metastases who have completed whole brain radiotherapy, stereotactic radiosurgery, or complete surgical resection will be eligible if they have remained clinically stable, asymptomatic, and off steroids for 1 month prior to enrollment.
Patients with clinically or radiologically unstable brain metastases are excluded from this clinical trial\r\n* Note: patients with stable brain metastases after treatment, for at least 3 months prior to enrolling on this trial, could participate in the study; patients should be off, or on a stable dose of steroids
Symptomatic 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.
Brain metastases, unless previously treated and asymptomatic and not progressive for 2 months.
Known central nervous system (CNS) metastases other than stable, treated brain metastases. Subjects with previously treated brain metastasis will be allowed if the brain metastasis has been stable by neuroimaging without steroid treatment for at least 3 months following prior treatment (radiotherapy or surgery).
Any known untreated brain metastases. Treated subjects must be stable 4 weeks after completion of treatment for brain metastases and image documented stability is required. Patients must have no clinical symptoms from brain metastases and must be either off of steroids or on a stable dose of steroids for at least 2 weeks prior to protocol enrollment. Patients with known leptomeningeal metastases are excluded, even if treated
Subject has known history of brain metastases unless previously treated and well controlled for at least 3 months (defined as stable clinically, no edema, no steroids)
Participants with known leptomeningeal metastases or untreated brain metastases. Participants with known brain metastases will be eligible if they have completed the primary brain therapy (such as whole brain radiotherapy, stereotactic radiosurgery, or complete surgical resection) and if they have remained clinically stable, asymptomatic, and off steroids for at least 28 days.
Any known, untreated, brain metastases. Treated subjects must be stable 4 weeks after completion of treatment for brain metastases and image documented stability is required. Patients must have no clinical symptoms from brain metastases and have not required systemic corticosteroids >10 mg/day prednisone or equivalent for at least 2 weeks prior to first dose of study drug.
Symptomatic central nervous system metastases; subjects with brain metastases that have been previously treated with whole body radiation therapy (WBXRT) and are stable for 6 weeks are allowed; (gamma or cyber knife treated lesions may enroll 2 weeks after completion if toxicities are resolved and no longer requiring steroids, patients with asymptomatic brain metastases are allowed after discussion with the study sponsor)
INCLUSION CRITERIA:\n\n          -  Age ? 18 years\n\n          -  Histologically confirmed diagnosis of unresectable stage III or metastatic melanoma\n             (stage IIIC to IV per American Joint Committee on Cancer [AJCC])\n\n          -  Documented evidence of BRAF V600 mutation.\n\n          -  Newly obtained tumor biopsy at baseline, and patient agrees to a mandatory biopsy at\n             the time of progression, if not medically contraindicated.\n\n          -  Evidence of measurable disease, as determined by RECIST v1.1.\n\n        INCLUSION CRITERIA for triple combinations:\n\n        Progressive disease following prior treatment with LGX818/MEK162 combination. PRINCIPAL\n        EXCLUSION CRITERIA Symptomatic or untreated leptomeningeal disease.\n\n          -  Symptomatic brain metastases. Patients previously treated or untreated for brain\n             metastases that are asymptomatic in the absence of corticosteroid therapy or on a\n             stable dose of steroids for four weeks are allowed to enroll. Brain metastases must be\n             stable at least 4 weeks with verification by imaging (e.g. brain MRI completed at\n             screening demonstrating no current evidence of progressive brain metastases). Patients\n             are not permitted to receive enzyme inducing anti-epileptic drugs.\n\n          -  Patients who have developed brain metastases during Part I of the study may continue\n             to Part II upon discussion with Novartis Medical Monitor. The brain metastasis must be\n             either asymptomatic or treated and stable for at least 4 weeks and on a stable or\n             tapering dose of steroids for at least 2 weeks. Patients with brain metastasis are not\n             eligible for the combination with LEE011.\n\n          -  Known acute or chronic pancreatitis.\n\n          -  History or current evidence of retinal vein occlusion (RVO) or current risk factors\n             for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity\n             or hypercoagulability syndromes);\n\n          -  Clinically significant cardiac disease including any of the following:\n\n          -  CHF requiring treatment (NYH grade ? 2),\n\n          -  LVEF < 50% as determined by MUGA scan or ECHO\n\n          -  History or presence of clinically significant ventricular arrhythmias or atrial\n             fibrillation\n\n          -  Clinically significant resting bradycardia\n\n          -  Unstable angina pectoris ? 3 months prior to starting study drug\n\n          -  Acute Myocardial Infarction (AMI) ? 3 months prior to starting study drug,\n\n          -  QTcF > 480 msec. Patients with any of the following laboratory values at\n\n        Screening/baseline:\n\n          -  Absolute neutrophil count (ANC) <1,500/mm3 [1.5 x 109/L]\n\n          -  Platelets < 100,000/mm3 [100 x 109/L]\n\n          -  Hemoglobin < 9.0 g/dL\n\n          -  Serum creatinine >1.5 x ULN or calculated or directly measured CrCl < 50% LLN (lower\n             limit of normal)\n\n          -  Serum total bilirubin >1.5 x ULN\n\n          -  AST/SGOT or ALT/SGPT > 2.5 x ULN, or > 5 x ULN if liver metastases are present\n\n        Additional exclusion criteria for the triple combinations:\n\n        LGX818/MEK162/BKM120:\n\n          -  Patients with fasting glucose > 120 mg/dL or 6.7 mmol/L, and HbA1c > 8 %.\n\n          -  Patient has any of the following mood disorders as judged by the\n\n        Investigator or a Psychiatrist:\n\n          -  Patient has a score ? 12 on the PHQ-9 questionnaire\n\n          -  Patient has ? CTCAE grade 3 anxiety\n\n        LGX818/MEK162/BGJ398:\n\n          -  History and/or current evidence of significant ectopic mineralization/ calcification\n             with the exception of calcified lymph nodes and asymptomatic vascular calcification.\n\n          -  Current evidence of corneal disorder/ keratopathy incl. but not limited to bullous/\n             band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjunctivits etc.,\n             confirmed by ophthalmologic examination\n\n        LGX818/MEK162/LEE011:\n\n          -  Patients with uncontrolled hypertension (please refer to WHO-ISHguidelines) are\n             excluded from study.\n\n          -  QTcF >450 ms for males and >470 ms for females Congenital long QT syndrome or family\n             history of unexpected sudden cardiac death and/or hypokalemia CTCAE Grade ? 3 and\n             magnesium levels below the clinically relevant lower limits at study entry\n\n          -  Current evidence of brain metastasis or brain metastasis detected by mandatory CT/MRI\n             at screening\n\n          -  PT/INR or aPTT > 1.5xULN\n\n        Other protocol-defined inclusion/exclusion criteria may apply.
Active brain 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)
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
Active brain metastases (e.g. stable for < 4 weeks)
The subject has active brain metastases, leptomeningeal or epidural disease (Note: subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain scans are not required to confirm eligibility)
Brain metastases unless resected or irradiated and stable >= 4 weeks
Clinically active brain metastases; radiological documentation of absence of active brain metastases at screening is required for all patients; prior evidence of brain metastasis successfully treated with surgery or radiation therapy will not be exclusion for participation as long as they are deemed under control at the time of study enrollment
Have active brain metastases. Subjects with brain metastases are allowed if they completed definitive brain therapy, are asymptomatic and radiologically stable, and if they are not currently receiving corticosteroids or radiation.
Active brain metastases (defined as neurologically stable for less than (<) 4 weeks and/or symptomatic and/or requiring treatment with steroids and/or leptomeningeal disease) Subjects must have completed any prior treatment for brain metastases >= 4 weeks prior to start of therapy (>= 2 weeks for stereotactic radiosurgery/gamma knife). Subjects who are neurologically stable on symptomatic therapy with anticonvulsants with low drug interaction risk or whose steroids are being tapered are eligible. Asymptomatic untreated brain metastases less than or equal to (<=) 1 cm of longest diameter are eligible
Patients with primary brain tumors are excluded. Patients with known progressive brain metastases determined by serial imaging or declining neurologic function in the opinion of the treating physician are not eligible. Patients with previously treated brain metastases are eligible, provided that the patient has not experienced a seizure or had a clinically significant change in neurological status within the 3 months prior to registration. All patients with previously treated brain metastases must be clinically stable for at least 1 month after completion of treatment and off steroid treatment for one month prior to study enrollment.
Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study
Brain metastases: brain metastases must have been treated at least 2 weeks prior to enrollment, be asymptomatic from brain metastases, stable on brain imaging, and not be receiving a supra-physiologic dose of steroids (> 10 mg prednisone daily or equivalent).
Subjects with treated brain metastases must have been treated with surgery and/or radiation therapy ? 21 days pre-study and must be clinically stable.
Patients with known brain metastases are NOT eligible for participation unless the brain metastases are treated (either with surgical excision, stereotactic radiosurgery or radiotherapy) and have been stable based on the physician’s assessment, the patient is asymptomatic and has discontinued corticosteroids if taken for that purpose
Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression. NOTE: Subjects previously treated for these conditions that have had stable central nervous system (CNS) disease (verified with consecutive imaging studies) for >1 months, 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 therapy 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 (EIAC) are allowed on study.
No active 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 treatment); no leptomeningeal disease
The subject has active brain metastases or epidural disease (Note: Subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible)
Symptomatic central nervous system metastases; subjects with brain metastases that have been previously treated and are stable for 4 weeks are allowed
Patient 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.
Patients with asymptomatic brain metastases are allowed, as long as they are stable and do not require treatment with anticonvulsants or escalating doses of steroids; maximum daily dose of steroids should be prednisone 20 mg or equivalent; radiation therapy for brain metastases must be completed at least 14 days prior to treatment on protocol
Patients with “treated and stable” brain lesions of a duration of >= 2 months may be enrolled
Note: Subjects with radiographically stable CNS metastases are defined as radiographically stable on the previous 2 brain imaging studies, asymptomatic, and off systemic steroids and anticonvulsants for at least 1 month; treatment with prophylactic anticonvulsants is permitted unless listed under prohibited medications
Patients who had treatment for their brain metastases greater than 1 month prior to treatment will be eligible; any brain metastases must be stable and not progressing prior to study entry
PHASE I: Participants with untreated or uncontrolled brain metastases are excluded from this clinical trial; patients with treated and stable (> 4 weeks) brain metastasis are allowed
Any known untreated brain metastases. Treated subjects must be stable for 4 weeks after completion of that treatment, with image documentation required. Patients must have no clinical symptoms from brain metastases and must be either off steroids or on a stable dose of steroids for at least 2 weeks prior to protocol enrollment. Patients with known leptomeningeal metastases are excluded, even if treated.
At the time of day 1 of the study, subjects with brain metastases must be asymptomatic for at least 4 weeks and:
Individuals with symptomatic or progressive brain metastases are ineligible; subjects with treated brain metastases are eligible if they have no radiographic or other signs of progression in the brain for >= 3 weeks after completion of local therapy; any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 3 weeks prior to study enrollment
Participants 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 dimension
Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression; should participants develop brain metastases while on trial and have clinical benefit from GSK1120212 and GSK2141795 otherwise, participants may continue on drug after clinical management of the brain metastases with the permission of the principal investigator; GSK1120212 and GSK2141795 should be restarted between 2 and 6 weeks after the last radiation treatment
Absence of brain metastases is not required. Patients must not have symptomatic brain metastatic disease. The patient may be symptomatically controlled on a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment.
Patients with “treated and stable” brain lesions of a duration of >= 2 months may be enrolled
No known or suspected brain metastases (NOTE: patients with treated epidural disease are allowed)
Active brain metastases: participants with previously diagnosed brain metastases are eligible if they have completed treatment at least one month prior to enrollment, are neurologically stable, and have recovery from effects of radiotherapy or surgery
All patients must undergo a CT or MRI of the brain within 42 days prior to registration; patients with asymptomatic brain metastases or previously treated brain metastases that are stable (i.e. not requiring corticosteroids) at the time of registration will be eligible
Patients with treated brain metastases that have been stable for 1 month are eligible; patients must be off steroids for week prior to starting study treatment
Subjects with known brain metastases who have completed whole brain radiotherapy, stereotactic radiosurgery, or complete surgical resection will be eligible if they have remained clinically stable, asymptomatic and off of steroids for 28 days.
Uncontrolled or symptomatic brain metastases that are not stable or require steroids, are potentially life-threatening or have required radiation within 28 days prior to first dose of study treatment.
Known brain metastases, unless stable for at least 28 days
Patients with treated, stable brain metastases are allowed to enroll; patients must be at least 4 weeks from brain radiation and off any medications used to treat brain metastases including steroids; patients are allowed to be on anti-epileptic medications that are not contraindicated
Patients with untreated brain metastases are excluded; however, patients with treated brain metastases are eligible if they are > 4 weeks from therapy completion (including radiation and/or surgery), are clinically stable at the time of study entry and are not receiving corticosteroid therapy at the time of study entry
Patients with known active, untreated brain metastases should be excluded from this clinical trial. Those with previously treated inactive brain metastases with no evidence of active disease documented on brain MRI at least 4 weeks after radiation and off all steroids may be eligible.
Any known untreated brain metastases. Treated subjects must be stable for 4 weeks after completion of that treatment, with image documentation required. Patients must have no clinical symptoms from brain metastases and must be either off steroids or on a stable dose of steroids for at least 2 weeks prior to protocol enrollment. Patients with known leptomeningeal metastases are excluded, even if treated.
Known uncontrolled brain metastases. Stable brain metastases either treated or being treated with a stable dose of steroids/anticonvulsants
The subject has active brain metastases or epidural disease; subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain scans are not required to confirm eligibility
Patients with stable brain metastases are eligible for this trial; stable brain metastases defined as stable disease for one month and not on active treatment including steroids
The participant has active brain metastases or epidural disease (Note: participants with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain scans are not required to confirm eligibility)
Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to enrollment in the study. Patients with a history of brain metastases must have a head CT with contrast to document stable disease prior to randomization in the study.
Subjects with known untreated brain metastases; subjects with known, treated brain metastases must be stable with no symptoms for four weeks after completion of that treatment, with image documentation required, and must either be off steroids or on a stable dose of steroids for at least two weeks prior to protocol enrollment; subjects with known leptomeningeal metastases are excluded, even if adequately treated; subjects without known brain metastases do not require radiologic imaging prior to enrollment
Previously treated NSCLC with asymptomatic brain metastases (eligible for Arm M) See additional details below
Previously untreated brain metastases; Note: patients with previously treated brain metastases are allowed as long as these are radiologically stable for >= 3 months and the patient is off steroids for >= 4 weeks
Subjects with known brain metastases will be eligible if they have completed the primary brain therapy (such as whole brain radiotherapy, stereotactic radiosurgery, or complete surgical resection) and if they have remained clinically stable, asymptomatic, and off of steroids for at least 28 days
Known brain metastases or cranial epidural disease unless adequately treated and stable for at least 4 weeks before first dose of study treatment.
Patients with known, untreated brain metastases; patients with treated (irradiated or resected) brain metastases are eligible if treatment was completed more than 28 days prior to study entry and if clinical neurologic function is stable
Patients with 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.
brain metastases are stable and have been previously treated with either whole-brain radiotherapy or gamma-knife surgery
Stable brain metastases either treated or being treated with a stable dose of steroids/ anticonvulsants, with no dose change within 28 days prior to the first dose of study drug, will be allowed.
Patients with untreated symptomatic brain metastases; patients with treated brain metastases will be allowed if brain imaging obtained within 30 days of trial enrollment reveals stable disease; patients with small asymptomatic brain metastasis are allowed to enroll; patients on steroids doses higher than 10 mg of prednisone (or its equivalent) are excluded
Has brain metastases with evolving neurologic symptoms or a steroid requirement.
Patients with treated brain metastases (received definitive radiation and/or underwent surgical resection) are eligible for therapy on this protocol; patients with clinical evidence of active brain metastases are ineligible for therapy on this protocol
History of brain metastases unless irradiated ? 2 weeks prior to first study treatment and stable without requirement of corticosteroids.
Active 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)
Brain metastases (except if all known lesions were previously treated with surgery or stereotactic radiosurgery and lesions, if still present, are confirmed stable for >= 2 weeks prior to enrollment, and are asymptomatic with no corticosteroid requirements for >= 2 weeks prior to randomization, and no enzyme inducing anticonvulsants for >= 2 weeks prior to randomization); brain MRI or CT is required at screening
10. Uncontrolled or severe concurrent medical condition (including uncontrolled brain metastases). Stable brain metastases either previously treated or being treated with a stable dose of steroids and/or anticonvulsants (no dose change within 28 days prior to the first dose of study drug) will be allowed.
Progressing brain metastases (unless previously treated and stable disease for a period of greater than or equal to 3 months on repeat MRI following definitive treatment).
At the time of day 1 of the study, patients with brain metastases must be asymptomatic and: 1) at least 8 weeks without tumor progression after any whole brain radiotherapy, 2) at least 4 weeks since craniotomy and resection or stereotactic radiosurgery, 3) at least 3 weeks without new brain metastases as evidenced by MRI
Participants with treated brain metastases are eligible for study participation; participants may not receive ongoing treatment with steroids at screening, anticonvulsants (at stable dose) are allowed
The subject has active brain metastases or epidural disease (note: subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain scans are not required to confirm eligibility)
Patients with brain metastases are allowed only if they are off systemic corticosteroids and stable for a minimum of 8 weeks
Patients with brain metastases which are stable and have been treated with surgery or irradiation will be eligible for this trial
Patients with gliomas or brain metastases who require corticosteroids or anticonvulsants must be on a stable dose of corticosteroids and seizure free for 1 month prior to enrollment; patients with known brain metastases should have had brain irradiation (whole brain or gamma knife) more than 4 weeks before starting the protocol; note that patients should have had their steroids tapered to low dose (i.e., < 1.5 mg of dexamethasone/day)
Patients with stable brain metastases are eligible for this trial. However, patients must not have required steroid treatment for their brain metastases within 30 days of Screening.
Symptomatic central nervous system metastases; subjects with brain metastases that have been previously treated and are stable for 4 weeks are allowed
Patients with untreated central nervous system metastases or local treatment of brain metastases within the last 6 months; patients with stable brain metastasis for 6 months post-intervention are eligible; subjects with chordoma will be eligible regardless of site of disease if other eligibility criteria are met
Patients must have a CT or MRI scan of the brain to evaluate for CNS disease within 42 days prior to registration; patient must not have brain metastases unless: (1) metastases have been treated and have remained controlled for at least 14 days following treatment or was not treated, but is asymptomatic, AND (2) patient has no residual neurological dysfunction off corticosteroids or anti-convulsants for at least 14 days
Patients with known active progressive brain metastases; patients with prior treated brain metastases are allowed, providing that they were not accompanied by seizures within the past year and that a baseline brain MRI scan prior to study entry demonstrates no current evidence of active brain metastases; all patients with prior treated brain metastases must be stable for > 1 months after treatment and off steroid treatment prior to study enrollment
Subjects with brain metastases are excluded if their brain metastases are: Symptomatic; Treated (surgery, radiation therapy) but not clinically and radiographically stable one month after local therapy, OR; Asymptomatic and untreated but > 1 cm in the longest dimension. Subjects with small (<= 1 cm in the longest dimension), asymptomatic brain metastases that do not need immediate local therapy can be enrolled. Subjects on a stable dose of corticosteroids for more than one month, or those who have been off corticosteroids for at least 2 weeks can be enrolled. Subjects must also be off of enzyme-inducing anticonvulsants for more than 4 weeks.
Brain metastasis, unless previously treated with surgery or stereotactic radiosurgery and the disease has been confirmed stable (i.e., no increase in lesion size, and stable or decreased doses of corticosteroids) for at least 6 weeks with two consecutive scans prior to Study Day 1 (Parts 1 and 2) or randomization (Part 3). (Enzyme inducing anticonvulsants are not allowed while subjects are on study treatment. Prior whole-brain radiation as adjuvant treatment is allowed.)
Patients who previously had brain metastases (screening not required) unless they have met all of the following criteria:
Patients with treated, stable brain metastases eligible providing treatment was ?4 weeks prior to initiation of study drug, and baseline CT or MRI negative for new brain metastases. Must not require therapy with corticosteroids.
Brain metastases are allowed if the patient is asymptomatic or previous steroid treatment was discontinued >= 6 weeks
Subject must not have known untreated brain or meningeal metastases. CT scans are not required to rule out brain or meningeal metastases unless there is a clinical suspicion of central nervous system disease. Subjects with treated brain metastases that are radiographically or clinically stable for at least 4 weeks after therapy and have no evidence of cavitation or hemorrhage in the brain lesion(s) are eligible, provided that they are asymptomatic and do not require corticosteroids (must have discontinued steroids at least one week prior to study drug administration).
Brain metastases that are untreated or symptomatic, or require any radiation, surgery, or steroid therapy to control symptoms from brain metastases within 14 days of first on-study thrombokinetic study; for patients with newly diagnosed brain metastases or unequivocal progression of brain metastases on screening scans, localized treatment (i.e., surgery, radiosurgery, and/or whole brain radiotherapy) is required before study enrollment; subjects with known brain metastases must have clinically controlled neurologic symptoms, defined as surgical excision and/or radiation therapy followed by 14 days of stable neurologic function prior to the first thrombokinetic procedure; patients with small brain metastases not symptomatic and deemed requiring treatment by managing clinicians or study investigators may be permitted to enroll on study
Patients with known brain metastases are excluded unless they have had definitive treatment (e.g. whole brain radiotherapy or surgery or stereotactic radiation) for brain metastases with evidence of stable/improved disease on repeat imaging following definitive treatment
Patients with brain or leptomeningeal metastases are allowed on study if the lesions are asymptomatic without neurological signs and clinically stable for at least 2 weeks
Patients with known brain metastases may be excluded from this study. However, patients may be eligible if scans show limited disease or repeat scans show stable disease in the opinion of the investigator and patients have no ill effect from the metastases.
Uncontrolled or symptomatic brain metastases that are not stable, require steroids, are potentially life-threatening or that have required radiation within 28 days prior to first dose of study treatment.
Any known symptomatic or untreated brain metastases requiring increase of steroid dose within 2 weeks prior to starting on study. Patients with treated brain metastases must be stable for 4 weeks after completion of that treatment. Patients must have no clinical symptoms from brain metastases and must be either off steroids or on a stable dose of steroids for at least 2 weeks prior to protocol enrollment. Patients with known leptomeningeal metastases are excluded, even if treated.
Patients with active brain metastases or carcinomatous meningitis or epidural disease are excluded from this clinical trial; subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation who are asymptomatic and have remained stable for 4 weeks and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain imaging with contrast-enhanced CT or MRI scans for subjects with known brain metastases is required to confirm eligibility
Known uncontrolled symptomatic brain metastases or cranial epidural disease; subjects previously treated and on stable dose of corticosteroids and/or anticonvulsants for > 10 days, or not requiring such medications, are eligible; baseline brain scans are not required to confirm eligibility
Patients with treated, stable brain metastases are allowed to enroll; patients must be at least 4 weeks from radiation and off any medications used to treat brain metastases including steroids; patients are allowed to be on antiepileptic medications that are not metabolized by cytochrome P450 3A4 or 2C19; patients with brain metastases must have stable brain imaging within 4 weeks prior to starting study
Subjects with brain metastases are excluded, unless a. All known lesions must be previously treated with surgery or stereotactic radiosurgery, and- b. Brain lesion(s), if still present, must be confirmed stable (i.e. no increase in lesion size) for ?90 days prior to first dose on study (must be documented with two consecutive MRI or CT scans using contrast), and c. Asymptomatic with no corticosteroids requirement for ? 30 days prior to first dose on study, and d. No enzyme-inducing anticonvulsants for ? 30 days prior to first dose on study.
For lung metastases, no more than 2 metastases treated in one setting
They have received standard anti-tumor treatment for their brain metastases without encephalopathy;
Active 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 randomisation)
Metastases in the brain or active epidural disease. (Note: patients with treated epidural disease are allowed);
Patients with asymptomatic brain metastases are allowed, as long as they are treated, stable, and do not require treatment with anticonvulsants or escalating doses of steroids; maximum daily dose of steroids should be prednisone 10 mg or equivalent; radiation therapy for brain metastases must be completed at least 14 days prior to treatment on protocol; patients with untreated brain metastases who are stable, asymptomatic and not requiring treatment with anticonvulsants or escalating doses of steroids are eligible
Symptomatic, untreated or unstable central nervous system or leptomeningeal metastases; (patients with treated and stable brain metastases [confirmed by 2 scans at least 4 weeks apart], with no evidence of cavitation or hemorrhage in the brain lesion are eligible provided that they are asymptomatic and do not require corticosteroids)
Patients with known symptomatic brain metastases requiring steroids and/or antiepileptic therapy; patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study treatment, and have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable; patients with leptomeningeal involvement are excluded
Stable, treated brain metastases are allowed; stable brain metastases are defined as stable on magnetic resonance imaging (MRI) 4 weeks after the completion of radiation, and currently asymptomatic no longer requiring corticosteroids for 2 weeks prior to the initiation of study drug
Patient has evidence of clinically unstable brain metastases (controlled and stable brain metastasis must be previously treated and asymptomatic)
Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms; participants with previously diagnosed brain metastases are eligible if they have completed treatment at least 4 weeks prior to registration, are neurologically stable and absence of new neurologic symptoms for the last 4 weeks prior to study entry, and have recovered from the effects of radiotherapy or surgery; any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 2 weeks before the first study drug; treatment for brain metastases may have included whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating physician
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
Known 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 enrollment
Patients with “treated and stable” brain lesions of a duration of >= 2 months may be enrolled
Patient must not have brain metastases present prior to initiation of initial therapy or PCI
Patients with brain metastases are allowed on this study (concurrent treatment with steroids is allowed)
Patients with brain metastases who require corticosteroids or non-enzyme inducing anticonvulsants must be on a stable dose of corticosteroids and seizure free for 1 month prior to enrollment; patients with known brain metastases should have completed brain irradiation (whole brain or gamma knife) more than 4 weeks before starting the protocol; patients on enzyme inducing anticonvulsants are not eligible; note that patients should have had their steroids tapered to low dose (i.e. < 1.5 mg of dexamethasone/day) due to the potential for higher dexamethasone doses to induce CYP3A4
Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Participants with clinically inactive brain metastases may be included in the study. Participants with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment (1 week for stereotactic radiotherapy)
Histologically or cytologically documented extensive disease. Brain metastases; must be asymptomatic or treated and stable off steroids and anti-convulsants for at least 1 month prior to study treatment.
Brain metastases unless asymptomatic and not requiring steroids for at least 4 weeks prior to start of study treatment (Patients with SCLC or LCNEC of lung only must have CT or MRI of brain during screening, and if metastases found, must have radiotherapy with 14 day washout or stereotactic radiotherapy or radio surgery with 7 day washout)
Participants with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study
All subjects with brain metastases, except those meeting the following criteria:\r\n* Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment \r\n* No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable)\r\n* Subjects must be either off steroids or on a stable or decreasing dose of =< 10 mg daily prednisone (or equivalent), excluding dexamethasone given as pre-treatment for trabectedin
Brain metastases allowed if asymptomatic, without edema, and not receiving corticosteroids or radiation
Brain metastases allowed if asymptomatic at study baseline. Patients with untreated brain metastases must not be on corticosteroids. If patients have neurological symptoms or signs due to CNS metastases, patients need to complete whole brain radiation or focal treatment at least 14 days before start of study treatment and be asymptomatic on stable or decreasing doses of corticosteroids at baseline.
Participants with known brain metastases who have completed whole brain radiotherapy, stereotactic radiosurgery or complete surgical resection, will be eligible if they have remained clinically stable, asymptomatic, and off steroids for one month.
Patients with brain metastases may participate if they have undergone appropriate treatment for the lesion(s), are at least two weeks post treatment without evidence for post-treatment progression, have no significant neurologic symptoms, and no longer require steroids for the reason of brain metastases