Neratinib Plus Capecitabine for the Treatment of Her2-Negative Metastatic Breast Cancer with Brain Metastases, FACT-5 Trial

Inclusion Criteria

• STEP 0: Male/female
• STEP 0: At least 18 years of age
• STEP 0: Histologically confirmed HER2 negative breast cancer determined from the most recent tumor sample (primary or metastatic), as per the current American Society of Clinical Oncology and College of American Pathologists HER2 testing guidelines
• STEP 0: For estrogen receptor (ER) positive breast cancer patients: prior treatment with a cyclin-dependent kinase (CDK)4/6 inhibitor and endocrine therapy in required in the metastatic settings. If a patient has received a CDK4/6 inhibitor plus endocrine therapy in the adjuvant settings and the cancer recurred while on the CDK4/6 inhibitor or within 12 months of the end of CDK4/6 inhibitor treatment, then the patient will eligible without getting a CDK4/6 inhibitor and endocrine therapy in the metastatic setting
• STEP 0: For triple negative breast cancer patients: no specific prior anti-cancer treatment is required
• STEP 0: Have radiological evidence of one or more brain metastases
• STEP 0: Ability to obtain an MRI
• STEP 0: Has a radiological evidence of primary breast tumor or metastasis (excluding sclerotic bone metastasis) outside of the brain which is accessible and feasible to a biopsy
• STEP 0: Willing to undergo a research core biopsy of the tumor tissue
• STEP 0: Considered to be medically fit for undergoing a biopsy
• STEP 0: Subjects anticipated by the investigator to be a candidate for systemic therapy immediately or in the future
• STEP 0: Ability to understand the investigational nature of the study and sign the informed consent
• STEP 1: Abnormally active HER2 signaling as determined by the CELsignia test on the tumor tissue
• STEP 1: Measurable brain metastases with at least one lesion > 5 mm in longest diameter
• STEP 1: Ability to obtain MRI
• STEP 1: No major surgery within 10 days prior to registration. Surgeries should be avoided any time after registration during the study treatment, but minor procedures like dental extractions and surgeries deemed important to maintain or improve patients’ quality of life and are allowed
• STEP 1: A minimum of 14 days since the last dose of chemotherapy except for the optional pre-step 1 capecitabine. If pre-step 1 optional capecitabine was administered, then a minimum of 7 days from the last dose of capecitabine is required before registration. There is no limit on the number of previous chemotherapy regimens for eligibility
• STEP 1: A minimum of 7 days since the last dose of any hormonal therapy (no limit on the number of previous hormonal regimens for eligibility) except fulvestrant. A minimum of 28 days since the last dose of fulvestrant before registration
• STEP 1: A minimum of 21 days since the last dose of targeted therapy (e.g., a CDK4/6 inhibitor, PI3 kinase inhibitors, etc.)
• STEP 1: A minimum of 7 days since the last fraction of extracranial radiation and has recovered from any acute toxic effects of radiation therapy
• STEP 1: A minimum of 30 days since the last dose of any investigational cancer treatment or any immunotherapy
• STEP 1: A minimum of 90 days after any radiation to the brain
• STEP 1: Eastern Cooperative Oncology Group (ECOG) performance status of 0 -2
• STEP 1: Left ventricular ejection fraction ≥ 50% at baseline
• STEP 1: Prior treatment-related major organ toxicities recovered to ≤ grade 1
• STEP 1: Absolute neutrophil count ≥ 1.5 x 10^9/L
• STEP 1: Hemoglobin ≥ 9.0 g/dL (90 g/L) * Blood transfusion is allowed to achieve the hemoglobin goal
• STEP 1: Platelets ≥ 100 x 10^9/L
• STEP 1: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN) (if no hepatic metastases). If hepatic tumor involvement, AST, and ALT ≤ 5 x ULN
• STEP 1: Bilirubin ≤ 1.5 x ULN
• STEP 1: Prothrombin time (PT)/international normalized ratio (INR) ≤ 1.5 x ULN if not on anticoagulants
• STEP 1: Calculated creatinine clearance ≥ 50 mL/min using the Cockcroft and Gault equation
• STEP 1: Post-menopausal, surgically sterile, or willing to use a reliable form of contraception while on the study and for 180 days after discontinuing either study treatment. The patients that can father children are willing to use highly effective contraception for at least 90 days following last dose of either study treatment
• STEP 1: Ability to understand the investigational nature of the study and sign the informed consent

Exclusion Criteria

• STEP 0: History of other malignancies other than the following: * Adequately treated non-melanoma skin cancer * Curatively treated in-situ cancer * Other solid tumors which have been curatively treated AND no evidence of recurrence in the last 1 year
• STEP 0: Gastrointestinal tract disease resulting in an inability to absorb oral medication
• STEP 0: Known hypersensitivity to the study drugs or their components
• STEP 0: Pregnant or breast-feeding
• STEP 0: Known or suspected leptomeningeal disease
• STEP 0: Known bleeding or coagulation issues, subject taking anticoagulants or having bleeding diathesis that may significantly increase the risk of bleeding during the biopsy. If the subject is on anticoagulation, perioperative management of anticoagulation should be done per institutional practice
• STEP 0: Chronic and concomitant use of strong or moderate CYP3A4 inhibitors and strong or moderate CYP3A4 inducers. These drugs should be stopped at least 14 days prior to registration to step 0
• STEP 0: Current uncontrolled medical conditions that could limit a subject’s ability to undertake study therapy
• STEP 0: Inflammatory bowel disease with diarrhea as a major component
• STEP 1: Normally active HER2 signaling as determined by the CELsignia test on the tumor tissue
• STEP 1: Inconclusive HER2 signaling testing by the CELsignia test on the tumor tissue
• STEP 1: Any brain radiation within 90 days prior to registration to step 1
• STEP 1: Resting blood pressure higher than systolic of 160 and/or diastolic of 110 mmHg or poorly controlled hypertension, history of labile hypertension, or poor compliance with anti-hypertensive medication
• STEP 1: Serious cardiac illness or condition including, but not limited to, clinically significant congestive heart failure, high-risk uncontrolled arrhythmias, unstable angina pectoris requiring medication, or clinically significant valvular heart disease
• STEP 1: History of pulmonary embolus or deep vein thrombosis diagnosed within the previous three months
• STEP 1: Current uncontrolled medical conditions that could limit a subject’s ability to undertake study therapy
• STEP 1: Known or suspected leptomeningeal disease
• STEP 1: Inflammatory bowel disease with diarrhea as a major component
• STEP 1: Chronic and concomitant use of strong or moderate CYP3A4 inhibitors and strong or moderate CYP3A4 inducers. These drugs should be stopped at least 14 days prior to registration to step 1
• STEP 1: Untreated or progressing brain metastasis with uncontrollable neurological symptoms