Neratinib, Capecitabine, and Trastuzumab Emtansine in Treating Patients with HER2-Positive Breast Cancer That Has Spread to the Brain

Inclusion Criteria

• INCLUSION CRITERIA - MAIN PROTOCOL (ALL COHORTS)
• Patients (men or women) must have histologically or cytologically confirmed invasive breast cancer, with metastatic disease; patients without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis by physical exam or radiologic study
• Invasive primary tumor or metastatic tissue confirmation of HER2-positive status, defined as presence of one or more of the following criteria: * Over-expression by immunohistochemistry (IHC) with score of 3+ (in > 30% of invasive tumor cells) AND/OR HER2 gene amplification (average of > 6 HER2 gene copies per nucleus or a FISH ratio [HER2 gene copies to chromosome 17 signals] of >= 2.0), according to guidelines and in keeping with past eligibility for ratio of >= 2.0 rather than the ratio of > 2.2 required by new guidelines * Note: Patients with a negative or equivocal overall result (FISH ratio of < 2.0 or =< 6.0 HER2 gene copies per nucleus) and IHC staining scores of 0, 1+, 2+ are not eligible for enrollment
• No increase in corticosteroid dose in the week prior to baseline brain imaging
• Age ≥ 18 years old
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Absolute neutrophil count >= 1,000/uL
• Platelets >= 100,000/uL
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN without liver metastases, or =< 5 x institutional ULN with liver metastases
• Creatinine =< 2.0 mg/dL or creatinine clearance >= 50 mL/min
• Left ventricular ejection fraction >= 50%, as determined by radionuclide ventriculograms (RVG) (MUGA) or echocardiogram within 60 days prior to initiation of protocol therapy
• Prior therapy: * Prior trastuzumab is allowed for all cohorts * Prior capecitabine is NOT allowed for participants enrolled to Cohorts 3A/3B ONLY * Prior lapatinib is allowed for Cohorts 1, 2, and 3B but NOT Cohort 3A * Prior T-DM1 is NOT allowed for Cohorts 4A and 4B, but is required for Cohort 4C; dose reductions on prior T-DM1 for Cohort 4C do not preclude enrollment on Cohort 4C; patients on 4C may have progressed on prior T-DM1 in the CNS or non-CNS sites and had to have tolerated therapy without significant toxicity that would preclude retreatment * No prior therapy with neratinib is allowed on any cohort * There is no limit to the number of previous lines of therapy (including chemotherapy, trastuzumab, and endocrine therapies); at least 2 weeks washout period post chemotherapy, any prior protocol therapy, lapatinib, other targeted or biologic or immunotherapy, or radiation therapy is required prior to study entry * No washout is required for hormonal therapy but concurrent hormonal therapy is not allowed for patients on study; the only exception to this is longstanding ovarian suppression in pre-menopausal patients, if this has been started >= 6 months prior to study enrollment; other hormonal therapies are not allowed while patients are on study
• The effects of neratinib, capecitabine, and T-DM1 on the developing human fetus are not known; for this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• Human immunodeficiency virus (HIV)-positive individuals on combination antiretroviral therapy are eligible for enrollment and will be monitored closely for potential pharmacokinetic interactions with neratinib
• Concomitant medications should be avoided (when possible) while on study
• Ability to understand and willingness to sign a written informed consent document
• For Cohorts 1, 3A/3B, 4B and 4C patients must have new or progressive measurable CNS lesions, as assessed by the patient's treating physician; this includes patients who have progressed after at least one line of standard local treatment for CNS disease (whole brain radiotherapy [WBRT], stereotactic radiosurgery [SRS], or surgical resection as below)
• In Cohort 2, eligible patients will include those who have CNS disease that is amenable for surgery (typically < 3 brain metastases and with planned resection by neurosurgery); these patients may include those who have received or not received previous treatment(s) for their CNS
• FURTHER ELIGIBILITY DETAILS FOR PATIENTS WITH PROGRESSIVE DISEASE (COHORTS 1, 3A/3B, 4B, 4C):
• Patients must have measurable CNS disease, defined as at least one parenchymal brain lesion that can be accurately measured in at least one dimension with longest dimension >= 10 mm by local radiology review; Note: measurable non-CNS disease is NOT required for study participation
• It is anticipated that some patients may have multiple progressive CNS lesions, one or several of which are treated with SRS or surgery with residual untreated lesions remaining; such patients are eligible for enrollment on this study providing that at least one residual (i.e. non-SRS-treated or non-resected) lesion is measurable (>= 10 mm); the location of the measurable lesion should be documented in the patient chart and case report form
• Patients who have had prior cranial surgery are eligible, provided that there is evidence of measurable residual or progressive lesions, and at least 2 weeks have passed since surgery; if a patient has surgical resection followed by WBRT, then there must be evidence of progressive CNS disease after the completion of WBRT
• Except for those in Cohort 4A where prior local CNS therapy is not allowed, patients who have had prior WBRT and/or SRS and then whose prior treated lesions have progressed thereafter are also eligible for all other cohorts; in this case, lesions which have been treated with SRS may be considered as target lesions if there is unequivocal evidence, in the opinion of the treating physician, of progression
• FURTHER ELIGIBILITY DETAILS FOR PATIENTS WITH OPERABLE DISEASE (COHORT 2):
• It is anticipated that patients who have intracranial disease amenable to surgery will have measurable CNS disease prior to study entry and to resection; however, this is not an eligibility requirement; measurable disease is also not required to continue on protocol subsequent to surgical resection
• For patients who undergo surgery, postoperative whole brain radiation therapy will not be allowed while patients are on study; patients will require discontinuation of neratinib if WBRT will be administered; however, if the treating provider feels that targeted radiosurgery (SRS, gamma knife, etc) would be of benefit postoperatively, patients may proceed with this and then begin neratinib AFTER radiation completes
• Further eligibility details for patients on Cohort 4A: All patients on Cohort 4A will not have received prior radiation or surgery to their brain; prior systemic therapy aimed to treat disease in the brain is allowed (i.e. prior systemic standard therapy or protocol systemic therapy for brain metastases [mets])
• Note: laboratory tests required for eligibility must be completed within 4 weeks prior to study entry; baseline measurements in the CNS must be documented from tests up to 21 days prior to planned start of protocol therapy unless not covered by insurance; if insurance coverage is an issue, a case by case approval of testing beyond this window may be approved by the overall study principal investigator (PI); other non-laboratory tests must be performed as indicated
• INCLUSION CRITERIA FOR CONTINUING THERAPY ON THE EXTENSION PHASE:
• Participants must have met all criteria to be enrolled on the main protocol for receipt of neratinib; at the time of enrollment on the extension phase for Cohorts 1 and 3, patients must have experienced progression of non-CNS disease by RECIST 1.1 criteria
• Cohorts 1 and 3: Participants must have stable disease or be responders (partial response [PR] or complete response [CR]) to neratinib in the CNS at the time of non-CNS progression
• Cohort 2: Participants must have progressive disease in CNS or non-CNS sites
• ECOG performance status 0-2 (all cohorts)
• Absolute neutrophil count > 1,000/uL
• Platelets > 100,000/uL
• Total bilirubin =< 1.5 x ULN
• AST (SGOT)/ALT (SGPT) < 3.0 x institutional upper limit of normal OR =< 5 x institutional upper limit of normal with liver metastases
• Creatinine =< 2 mg/dL or creatinine clearance >= 50 mL/min
• The effects of trastuzumab, capecitabine, and neratinib on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• Left ventricular ejection fraction >= 50%, as determined by RVG (MUGA) or echocardiogram within 60 days prior to initiation of extension phase therapy (all cohorts)
• Ability to understand and the willingness to sign a written informed consent document (all cohorts)

Exclusion Criteria

• EXCLUSION CRITERIA - MAIN PROTOCOL
• Participants who have had chemotherapy or radiotherapy (including investigational agents) within 2 weeks prior to entering the study or those who have not recovered adequately from adverse events due to agents administered more than 4 weeks earlier (excluding alopecia); washout from trastuzumab or hormonal therapy is not required
• Participants who are currently receiving any other investigational agents
• History of severe allergic reactions or intolerability attributed to compounds of similar chemical or biologic composition to neratinib (all cohorts), capecitabine for Cohorts 3A/3B, and T-DM1 for Cohorts 4A-4C
• Concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs), including phenytoin, carbamazepine, oxcarbazepine, fosphenytoin, phenobarbital, pentobarbital, or primidone
• Patients who are receiving any cancer-directed concurrent therapy, such as concurrent chemotherapy, radiotherapy, or hormonal therapy while on study; concurrent treatment with bisphosphonates and denosumab is allowed for bony metastases but should be started before the first dose of neratinib
• Any prior treatment with capecitabine for patients enrolled to Cohorts 3A/3B, prior lapatinib for participants on Cohort 3A, and T-DM1 for Cohorts 4A-4B
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• For Cohorts 4A, 4B, and 4C: Patients with myocardial infarction or cardiomyopathy onset within the last 6 months are excluded
• Active hepatitis B or hepatitis C with abnormal liver function tests (Cohorts 4A-4C); positive hepatitis B (hepatitis B surface antigen and antibody) and/or hepatitis C (hepatitis C antibody test) as indicated by serologies conducted =< 3 months prior to registration if liver function tests are outside of the normal institutional range * Note: Patients with positive hepatitis B or C serologies without known active disease are eligible if they meet all laboratory requirements; patients with laboratory evidence of vaccination to hepatitis B (e.g., positive antibodies) are also eligible
• Active liver disease from autoimmune disorders or sclerosing cholangitis
• Lung disease from etiology other than metastatic breast cancer resulting in dyspnea at rest (4A-4C)
• More than two seizures over the last 4 weeks prior to study entry
• Patients with known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign body; however, head CT with contrast is allowed in place of MRI at baseline and throughout the study if MRI is contraindicated and a participant’s CNS lesions are clearly measurable on the head CT
• Those with leptomeningeal metastases as the only site of CNS disease
• Significant malabsorption syndrome or inability to tolerate oral medications
• Any predisposing chronic condition resulting in baseline grade 2 or higher diarrhea
• Inability to comply with study and/or follow-up procedures
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with neratinib; negative urine pregnancy test is required for women of childbearing potential within 4 weeks of planned treatment start
• Individuals with a history of a different active malignancy are ineligible
• EXCLUSION CRITERIA FOR CONTINUING THERAPY ON THE EXTENSION PHASE:
• Exclusion criteria will include all criteria listed for the main protocol
• History of allergic reactions attributed to trastuzumab (Cohorts 1, 3) that were not treatable/preventable with pre-medications or desensitization protocols