Capecitabine and Neratinib in Treating Patients with HER2 Positive Stage IV Breast Cancer

This phase Ib / II trial studies the side effects and best dose of capecitabine when given together with neratinib and to see how well it works in treating patients with HER2 positive stage IV breast cancer. Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Neratinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving capecitabine and neratinib may work better than capecitabine alone in treating patients with breast cancer.

Inclusion Criteria

• Histologically confirmed metastatic breast cancer (MBC), current stage IV
• Documented HER2 overexpression (immunohistochemistry [IHC] 3+ or gene-amplified tumor with fluorescence in situ hybridization [FISH] ratio of >= 2.0)
• For phase Ib, any line of prior treatments is permitted including prior neratinib and capecitabine
• For phase II, up to 4 prior chemotherapy-based treatments are allowed; patients must have had prior trastuzumab-based therapy; prior neratinib treatment is not permitted; prior capecitabine is allowed, if not combined with neratinib
• Measurable or non-measurable disease is permitted as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) for phase 1b; for phase 2, patients must have measurable disease as defined in RECIST v1.1
• Left ventricular ejection fraction (LVEF) >= 50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO)
• Eastern Cooperative Oncology Group (ECOG) status of 0 to 1
• White blood cell (WBC) count of >= 3000/ul
• Absolute neutrophil count (ANC) >= 1000/ul
• Platelets >= 50,000/ul
• Hemoglobin >= 8.0 g/dl
• Bilirubin =< 1.5 mg/dl
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x upper limit of normal (ULN) (=< 5.0 x ULN if liver metastases are involved)
• Creatinine =< 1.5 mg/dl
• Patients with “treated and stable” brain lesions of a duration of >= 2 months may be enrolled
• Negative beta-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after menopause
• Women of childbearing potential must agree and commit to the use of a highly effective method of contraception as determined to be acceptable by the investigator, from the time of informed consent until 28 days after the last dose of the investigational product; men must agree and commit to use a barrier method of contraception while on treatment and for 3 months after last dose of investigational products
• Provide written, informed consent to participate in the study and follow the study procedures

Exclusion Criteria

• Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmia
• Received prior therapy resulting in a cumulative epirubicin dose > 900 mg/m^2 or cumulative doxorubicin dose > 450 mg/m^2; if another anthracycline or more than one anthracycline has been used, the cumulative dose must not exceed the equivalent of 450 mg/m^2 doxorubicin
• Any major surgery =< 28 days prior to the initiation of investigational products, or received anti-cancer therapy (including chemotherapy, biological therapy, hormonal therapy, investigational agents, or other anti-cancer therapy) administered =< 14 days prior to the initiation of investigational products
• Received radiation therapy =< 14 days prior to initiation of investigational products
• Corrected QT (QTc) interval > 450 ms for men or 470 ms for women, or known history of QTc prolongation or Torsades de Pointes
• Active hepatitis B or C
• Active infection or unexplained fever > 38.5 degrees Celsius (C) (> 101.3 degrees Fahrenheit [F]) within 2 weeks prior to enrollment
• Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn’s disease, malabsorption, or grade >= 2 diarrhea of any etiology screening)
• Known dihydropyrimidine dehydrogenase deficiency
• Known hypersensitivity to 5-fluorouracil or to any component of the investigational products or compounds of similar chemical composition
• Pregnant patients or currently breast-feeding

PRIMARY OBJECTIVES:

I. To establish the safety and tolerability of capecitabine 7/7 and neratinib. (Phase Ib)

II. To assess for efficacy of capecitabine 7/7 and neratinib. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluative safety and tolerability. (Phase II)

II. To assess for progression-free survival of capecitabine 7/7 and neratinib. (Phase II)

EXPLORATORY OBJECTIVES:

I. To collect research blood (i.e.: cell-free deoxyribonucleic acid [cfDNA]) to correlate with the response during treatment. (Phase II)

II. To assess quality of life while on the treatment with periodic questionnaires. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of capecitabine followed by a phase II study.

Patients receive neratinib orally (PO) once daily (QD) on days 1-28 and capecitabine PO every 12 hours (Q12H) on days 1-7 and 15-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Chau Thanh Dang