Inclusion Criteria\n\n        Histologically confirmed HER+ breast carcinoma, with HER+ defined by in situ\n        hybridization (ISH) or fluorescence in situ hybridization (FISH) methodology\n\n        Received previous treatment with trastuzumab, pertuzumab, and T-DM\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 .\n\n        At least  years of age at time of consent\n\n        Eastern Cooperative Oncology Group Performance Status (ECOG PS)  or \n\n        Adequate hepatic and renal function\n\n        Left ventricular ejection fraction (LVEF) ? %\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               . 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               . 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 ?  days prior to first dose of\n             study treatment, time since stereotactic radiosurgery (SRS) is ?  days prior to first\n             dose of study treatment, or time since surgical resection is ?  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          . lapatinib within  months of starting study treatment (except in cases where\n             lapatinib was given for ?  days and was discontinued for reasons other than disease\n             progression or toxicity)\n\n          . neratinib, afatinib, or other investigational HER/epidermal growth factor receptor\n             (EGFR) tyrosine kinase inhibitor (TKI) at any time previously\n\n          . previously been treated with capecitabine for metastatic disease except in cases where\n             capecitabine was given for <  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  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 > . 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 >  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
Patients with brain metastases are eligible if these lesions have been previously treated and the patients have no clinical or radiographic evidence of progression within  days prior to enrollment.
Known brain metastases (unless previously treated and well controlled for a period of at least  months).
For Group A: Subjects with a history of brain metastases are ineligible. This includes previously treated brain metastases. For Group B (subjects with AML): Active symptomatic CNS involvement of AML. Subjects with previously treated leptomeningeal disease that has been effectively treated are eligible.
Patients with central nervous system metastases are excluded; Note: subjects with previously treated (radiotherapy or surgery) brain metastasis that have been stable without steroid treatment for at least  months following prior treatment may be enrolled
Patients with previously untreated brain metastases (including parenchymal, meningeal or dural-based central nervous system [CNS] lesions) are excluded; however, patients with previously treated (surgery, radiation or both), clinically inactive brain metastases, who have not received corticosteroid therapy within three weeks of starting protocol therapy, are eligible
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
The participant has active brain metastases or epidural disease; participants with brain metastases previously treated with whole brain radiation or radiosurgery or participants with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least  weeks before starting study treatment are eligible; participants with treated brain metastasis should not take enzyme-inducing anticonvulsive therapies (EIACDs) within  weeks of registration, though non-enzyme inducing anticonvulsive drugs such as levetiracetam are allowed; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least  months before starting study treatment; baseline brain imaging with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans for participants with known brain metastases is required to confirm eligibility
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  months prior to screening without requirement of corticosteroids or anticonvulsants are permitted
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  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  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  weeks before starting study treatment
Patients can have concomitant brain metastases as long as they do not require active treatment or have been treated
Patients with known brain metastases unless treated with an appropriate modality with no evidence of progression/recurrence for >  months
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  days prior to enrollment
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  month ( weeks).
Brain metastases unless previously treated and well controlled for at least  months
Subjects with previously treated brain or central nervous system (CNS) metastases are eligible provided that the subject has recovered from any acute effects of radiotherapy and is not requiring steroids, and any whole brain radiation therapy was completed at least  weeks prior to study drug administration, or any stereotactic radiosurgery was completed at least  weeks prior to study drug administration; liver metastases will not be included as part of the radiated lesions to be treated
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  months post-surgery. For brain metastases treated with whole brain or stereotactic radiation therapy, brain imaging must be stable >  months. All subjects previously treated for brain metastases must be stable off corticosteroid therapy for at least  days prior to CD.
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  month ( weeks)
Subjects with no brain metastases or a history of previously treated brain metastases who have been treated by surgery or stereotactic radiosurgery (SRS) at least  weeks prior to enrollment and have a baseline MRI that shows no evidence of active intracranial disease
A history of previously treated brain metastases is allowed, provided that at least  days have lapsed between radiation and initiation of pembrolizumab; any brain metastasis >=  mm or causing symptoms must be treated with local therapy (i.e. radiation or surgical resection, as clinically appropriate) prior to study enrollment; any lesion present at the time of whole brain radiotherapy (WBRT) or included in the stereotactic radiotherapy field (or within  mm of the treated lesion) will NOT be considered evaluable unless it is new or documented to have progressed since treatment
Brain metastases unless previously treated and well controlled for at least  months
Subjects with brain metastases should be excluded from this clinical trial unless all the metastasis are treated surgically or radio-surgically
A history of previously treated brain metastases is allowed, provided that at least  days have lapsed between radiation and initiation of MK-; any lesion present at the time of whole-brain radiotherapy (WBRT) or included in the stereotactic radiotherapy field (or within mm of the treated lesion) will NOT be considered evaluable unless it is new or documented to have progressed since 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  weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least  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)
Subjects with brain metastases are excluded from this clinical trial unless all the metastases are adequately treated with surgery or radiation\r\n* Follow-up imaging showing treatment adequacy is not required
Known brain metastases, unless previously treated and asymptomatic for  months and not progressive in size or number for  months
Subjects with no brain metastases or a history of previously treated brain metastases who:\r\n* Have been treated by surgery or stereotactic radiosurgery (SRS) at least  weeks prior to enrollment\r\n* AND have a baseline magnetic resonance imaging (MRI) that shows no evidence of active intercranial disease\r\n* AND have not had treatment with steroids for brain metastases within  week of study enrollment
Patients may not have previously been treated with >  course of radiotherapy to the brain
Patients may not have previously been treated with radiosurgery to the brain
Known uncontrolled brain, leptomeningeal or epidural metastases (unless treated and well controlled for at least  weeks prior to Cycle  Day ). Controlled brain metastases that require continuous high dose corticosteroid use within  weeks of Day
Previously untreated brain metastases. Patients who have received radiation or surgery for brain metastases are eligible if therapy was completed at least  weeks previously and there is no evidence of central nervous system disease progression, mild neurologic symptoms, and no requirement for chronic corticosteroid therapy.
Known brain metastases (unless previously treated and well controlled for a period of > or =  months).
Brain metastases considered unstable as: a. without confirmed stability over  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  days.
Subjects with no brain metastases or a history of previously treated brain metastases who:\r\n* Have been treated by surgery or stereotactic radiosurgery (SRS) at least  weeks prior to enrollment\r\n* AND have a baseline magnetic resonance imaging (MRI) that shows no evidence of active intracranial disease\r\n* AND have not had treatment with steroids within  week of study enrollment\r\n* Neuroblastoma (NB): Concurrent use of steroids as a supportive medication, e.g. for appetite stimulation is allowed, but must comply with the doses listed
Subjects with previously treated brain metastases who are free of central nervous system (CNS) symptoms and are >  months from treatment of brain metastases are eligible
Patients who have previously been treated with whole brain radiation
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  weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least  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
Known brain metastases, unless stable or previously treated.
Brain metastases, unless previously treated and asymptomatic and not progressive for  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  months following prior treatment (radiotherapy or surgery).
Subject has known history of brain metastases unless previously treated and well controlled for at least  months (defined as stable clinically, no edema, no steroids)
Subjects with active central nervous system (CNS) disease are excluded; patient with brain metastases previously treated with surgery or radiation therapy and with confirmed stable disease (SD) for >=  weeks are allowed
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  weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least  months before starting study treatment; baseline brain scans are not required to confirm eligibility)
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  months prior to registration. All patients with previously treated brain metastases must be clinically stable for at least  month after completion of treatment and off steroid treatment for one month prior to study enrollment.
Subjects with active central nervous system (CNS) disease are excluded; patient with brain metastases previously treated with surgery or radiation therapy and with confirmed stable disease (SD) for >=  weeks are allowed
Subjects with treated brain metastases must have been treated with surgery and/or radiation therapy ?  days pre-study and must be clinically stable.
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  weeks before starting study treatment are eligible)
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  weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least  months before starting study treatment; (baseline brain imaging with contrast-enhanced CT or magnetic resonance imaging [MRI] scans for subjects with known brain metastases is required to confirm eligibility)
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  weeks before starting study treatment are eligible); neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least  months before starting study treatment (Baseline brain imaging with contrast-enhanced CT or magnetic resonance imaging [MRI] scans for subjects with known brain metastases is required to confirm eligibility)
Expansion A:\r\n* Brain metastases or leptomeningeal not previously treated with radiation or surgery
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  weeks after radiation and off all steroids may be eligible.
Brain metastases are excluded unless: \r\n* All known lesions were previously treated with surgery or stereotactic surgery (whole-brain radiation is not allowed unless given after definitive treatment with surgery or stereotactic surgery), AND \r\n* Brain lesion(s), if still present, must be confirmed stable (i.e., no increase in lesion size) for >=  weeks prior to D of study treatment (stability must be confirmed with two consecutive magnetic resonance image [MRI] or computed tomography [CT] scans with contrast, AND \r\n* Asymptomatic with no corticosteroid requirements for >=  weeks prior to D of study treatment, AND \r\n* Treatment with any cytochrome P (CYP) enzyme inducing anticonvulsants occurred <  weeks prior to D of study treatment \r\nNOTE: if study subject has history of brain metastasis, but currently has no evidence of disease in brain (NED), confirmation by two consecutive scans separated by >=  weeks prior to D of treatment is required
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  weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least  months before starting study treatment; baseline brain scans are not required to confirm eligibility
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  weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least  months before starting study treatment; baseline brain scans are not required to confirm eligibility)
Subjects with no brain metastases or a history of previously treated brain metastases who:\r\n* Have been treated by surgery or stereotactic radiosurgery (SRS) at least  weeks prior to enrollment\r\n* AND have a baseline magnetic resonance imaging (MRI) that shows no evidence of active intracranial disease\r\n* AND have not had treatment with steroids within  week of study enrollment\r\n* Neuroblastoma (NB): Concurrent use of steroids as a supportive medication, e.g. for appetite stimulation is allowed, but must comply with the doses listed
Previously untreated brain metastases; Note: patients with previously treated brain metastases are allowed as long as these are radiologically stable for >=  months and the patient is off steroids for >=  weeks
Subjects with previously treated progressing brain metastases are excluded from the study
Subjects with no brain metastases or a history of previously treated brain metastases who:\r\n* Have been treated by surgery or stereotactic radiosurgery (SRS) at least  weeks prior to enrollment\r\n* AND have a baseline magnetic resonance imaging (MRI) that shows no evidence of active intracranial disease\r\n* AND have not had treatment with steroids for brain metastases within  week of study enrollment
brain metastases are stable and have been previously treated with either whole-brain radiotherapy or gamma-knife surgery
Patients with known brain metastases unless treated with an appropriate modality with no evidence of progression/recurrence for >  months
The participant has active brain metastases or epidural disease; participants with stable brain metastases previously treated with whole brain radiation or radiosurgery or participants with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least  weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least  months before starting study treatment; baseline brain imaging with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans for participants with known brain metastases is required to confirm eligibility
Progressing brain metastases (unless previously treated and stable disease for a period of greater than or equal to  months on repeat MRI following definitive treatment).
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  weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least  months before starting study treatment; baseline brain scans are not required to confirm eligibility)
Patients with brain metastases unless all of their metastatic brain lesions have been resected or treated with stereotactic radiotherapy with gamma rays and they are off corticosteroids; patient should not have significant brain edema; patients with spinal cord compression and leptomeningeal disease; patients with treated central nervous system (CNS) metastases are not eligible for the neoadjuvant treatment cohort in Phase II; no major surgery or radiation therapy within  days before starting treatment
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  weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least  months before starting study treatment; baseline brain imaging with contrast-enhanced CT or magnetic resonance imaging (MRI) scans for subjects with known brain metastases is required to confirm eligibility
Subjects with no brain metastases or a history of previously treated brain metastases who:\r\n* Have been treated by surgery or stereotactic radiosurgery (SRS) at least  weeks prior to enrollment\r\n* AND have a baseline magnetic resonance imaging (MRI) that shows no evidence of active intra cranial disease\r\n* AND have not had treatment with steroids within  week of study enrollment\r\n* Neuroblastoma (NB): Concurrent use of steroids as a supportive medication, e.g. for appetite stimulation is allowed
Patients who previously had brain metastases (screening not required) unless they have met all of the following criteria:
Central nervous system metastases\r\n* Note: Subjects with previously treated (radiotherapy or surgery) brain metastasis that have been stable without steroid treatment for at least  months following prior treatment may be enrolled
For patients with brain metastases, the following criteria must be met: Previously untreated brain metastases that are asymptomatic and not requiring steroids are permitted. Previously treated brain metastases are permitted if most recent CNS radiographic imaging demonstrates no evidence of CNS disease progression For patients with previously untreated brain metastases, Central Nervous System (CNS) imaging is required at the time of disease imaging throughout treatment.
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  weeks and do not require steroid treatment for at least  weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least  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 >  days, or not requiring such medications, are eligible; baseline brain scans are not required to confirm eligibility
Patients with no brain metastases or a history of previously treated brain metastases who have been treated by surgery or stereotactic radiosurgery at least  weeks prior to enrollment and have a baseline MRI that shows no evidence of active intracranial disease and have not had treatment with steroids within  week of study enrollment