Neratinib with or without Fulvestrant in Metastatic HER2-Negative but HER2 Mutant Breast Cancer

Inclusion Criteria

• INCLUSION CRITERIA FOR PRE-REGISTRATION (PATIENTS WITH UNKNOWN HER2 MUTATION STATUS TO HAVE TUMOR TISSUE SCREENED CENTRALLY BY WASHINGTON UNIVERSITY [WASH U] GENOMICS AND PATHOLOGY SERVICES [GPS] LABORATORY):
• Histologically or cytologically confirmed HER2-negative (0 or 1+ by immunohistochemistry [IHC] or non-amplified by fluorescent in situ hybridization [FISH]) breast cancer that is stage IV
• Agree to provide archival tumor material for research
• There is no limitation on the number of prior lines of systemic therapy
• Presence of measurable or non-measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 is acceptable, except to be eligible for the Part II fulvestrant-naive ER+ cohort, at least one measurable disease by RECIST 1.1 is required
• Eastern Cooperate Oncology Group (ECOG) performance status =< 2
• Serum creatinine: =< 1.5 x upper limit of normal (ULN) within 8 weeks of pre-registration
• Child-Pugh class A if with liver disease within 8 weeks of pre-registration
• Able to understand and willing to sign an Institutional Review Board (IRB) approved written informed consent document
• Note: HER2 mutation testing may be performed while the patient is receiving active systemic therapy for metastatic breast cancer so that the result can be used to determine eligibility for study drug therapy in the future
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Tumor tissue tested positive for HER2 mutation; mutations outside the list will be assessed on a case-by-case basis by the study team to determine eligibility * Note: HER2 mutations listed and detected by Guardant360 are also eligible
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Agree to provide archival tumor material for research
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): ECOG performance status =< 2
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Absolute neutrophil count: >= 1.5 x 10^9/L (1500/mm^3) within 2 weeks of registration
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Platelet count: >= 100 x 10^9/L (100,000/mm^3) within 2 weeks of registration
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Serum creatinine: =< 1.5 x ULN within 2 weeks of registration
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Child-Pugh class A if with liver disease within 2 weeks of registration
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): The patient must have completed radiation therapy and be at least 1 week from the last systemic therapy administration, with adequate recovery of bone marrow and organ functions, before starting neratinib
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Presence of disease progression on the most recent disease evaluation
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Patients with known treated brain metastasis are eligible, but must have received radiation and be off steroids and stable (without evidence of disease progression by imaging or exam) for 3 months
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Corrected QT (QTc) interval =< 450 msec for men or =< 470 msec for women within 2 weeks of registration
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) within 4 weeks of registration
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Women of childbearing 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 must inform her treating physician immediately; men must agree and commit to use a barrier method of contraception while on treatment and for 3 months after the last dose of the investigational product
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Able to understand and willing to sign an IRB approved written informed consent document
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): There is no limitation on the number of prior lines of systemic therapy
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): To be eligible for the Part II fulvestrant-naive ER+ cohort, prior treatment with fulvestrant is not allowed; in addition, ER and/or progesterone receptor (PR) positivity by institutional standard is required on pathology from the most recent tumor specimen if biopsy was done unless the tissue source (for example, pleural effusion or ascites or bone biopsy) may yield false negative ER and/or PR result, in which case the pathology from an earlier time point could be used and a discussion with the study chair is required
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): To be eligible for the Part II fulvestrant-treated ER+ cohort, prior disease progression on fulvestrant is required; in addition, ER and/or PR positivity by institutional standard is required on pathology from the most recent tumor specimen unless the tissue source (for example, pleural effusion or ascites or bone biopsy) may yield false negative ER and/or PR result, in which case the pathology from an earlier time point could be used and a discussion with the study chair is required
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLINICAL LABORATORY IMPROVEMENT ACT [CLIA] CERTIFIED LOCATION): Histologically or cytologically confirmed HER2-negative (0 or 1+ by IHC or non- amplified by FISH) breast cancer that is stage IV
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): Tumor tissue or circulating tumor deoxyribonucleic acid (DNA) tested positive for HER2 mutation; mutations outside the list will be assessed on a case-by-case basis by the study team to determine eligibility
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): Presence of measurable or non-measurable disease by RECIST 1.1 is acceptable, except to be eligible for the Part II fulvestrant-naive ER+ cohort, at least one measurable disease by RECIST 1.1 is required
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): ECOG performance status =< 2
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): Absolute neutrophil count: >= 1.5 x 10^9/L (1500/mm^3) within 2 weeks of registration
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): Platelet count: >= 100 x 10^9/L (100,000/mm^3) within 2 weeks of registration
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): Serum creatinine: =< 1.5 x ULN within 2 weeks of registration
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): Child-Pugh class A if with liver disease within 2 weeks of registration
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): The patient must have completed radiation therapy and be at least 1 week from the last systemic therapy administration, with adequate recovery of bone marrow and organ functions, before starting neratinib
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): Presence of disease progression on the most recent disease evaluation
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): Patients with known treated brain metastasis are eligible, but must have received radiation and be off steroids and stable (without evidence of disease progression by imaging or exam) for 3 months
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): QTc interval =< 450 msec for men or =< 470 msec for women within 2 weeks of registration
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): LVEF >= institutional LLN within 4 weeks of registration
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): Women of childbearing 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 must inform her treating physician immediately; men must agree and commit to use a barrier method of contraception while on treatment and for 3 months after the last dose of the investigational product
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): Able to understand and willing to sign an IRB approved written informed consent document
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): There is no limitation on the number of prior lines of systemic therapy
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): To be eligible for the Part II fulvestrant-naive ER+ cohort, prior treatment with fulvestrant is not allowed; in addition, ER and/or PR positivity by institutional standard is required on pathology from the most recent tumor specimen if biopsy was done unless the tissue source (for example, pleural effusion or ascites or bone biopsy) may yield false negative ER and/or PR result, in which case the pathology from an earlier time point could be used and a discussion with the study chair is required
• INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): To be eligible for the Part II fulvestrant-treated ER+ cohort, prior disease progression on fulvestrant is required; in addition, ER and/or PR positivity by institutional standard is required on pathology from the most recent tumor specimen unless the tissue source (for example, pleural effusion or ascites or bone biopsy) may yield false negative ER and/or PR result, in which case the pathology from an earlier time point could be used and a discussion with the study chair is required

Exclusion Criteria

• EXCLUSION CRITERIA FOR PRE-REGISTRATION:
• Testing for LVEF is not required for pre-registration, but patient must not have a recent LVEF < LLN or have symptoms of congestive heart failure
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Acute or currently active hepatic or biliary disease requiring antiviral therapy (with the exception of Gilbert’s syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease per investigator assessment)
• History of significant cardiac disease, cardiac risk factors, or uncontrolled arrhythmias
• Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest
• EXCLUSION CRITERIA FOR REGISTRATION: Currently receiving any other investigational agents or systemic cancer therapy
• EXCLUSION CRITERIA FOR REGISTRATION: Currently taking medications and herbal or dietary supplements that are strong cytochrome P450 (CYP) family 3, subfamily A, polypeptide 4 (3A4) inducers or inhibitors; a washout period of at least 5 days is required and must have been completed prior to the start of neratinib if the patient was taking any of these agents; if unavoidable, patients taking CYP3A4 inhibitors should be monitored closely
• EXCLUSION CRITERIA FOR REGISTRATION: 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
• EXCLUSION CRITERIA FOR REGISTRATION: Acute or currently active hepatic or biliary disease requiring antiviral therapy (with the exception of patients with Gilbert’s syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease per investigator assessment)
• EXCLUSION CRITERIA FOR REGISTRATION: Pregnant and/or breastfeeding
• EXCLUSION CRITERIA FOR REGISTRATION: History of significant cardiac disease, cardiac risk factors, or uncontrolled arrhythmias
• EXCLUSION CRITERIA FOR REGISTRATION: Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest
• EXCLUSION CRITERIA FOR REGISTRATION: Experiencing grade 2 or greater diarrhea
• EXCLUSION CRITERIA FOR REGISTRATION: Prior treatment with neratinib
• EXCLUSION CRITERIA FOR REGISTRATION: Child-Pugh class B or C liver dysfunction