Metastatic Breast Carcinoma Clinical Trial
Official title:
A Phase 1b Study of Neratinib, Pertuzumab, and Trastuzumab With Taxol (3HT) in Metastatic and Locally Advanced Breast Cancer, and Phase II Study of 3HT Followed by AC in HER2 + Primary IBC, and Neratinib With Taxol (NT) Followed by AC in HR+ /HER2- Primary IBC
This phase I/II trial studies the side effect and best dose of neratinib and to see how well it works with paclitaxel and with or without pertuzumab and trastuzumab before combination chemotherapy in treating patients with breast cancer that has spread to other places in the body (metastatic). Neratinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with pertuzumab and trastuzumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as paclitaxel, doxorubicin, and cyclophosphamide, 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. Giving neratinib, pertuzumab, trastuzumab, paclitaxel and combination chemotherapy may work better in treating patients with breast cancer.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of neratinib in combination with paclitaxel, pertuzumab, and trastuzumab in HER2-positive (HER2+) metastatic or locally advanced (stage III) breast cancer within 2 cycles. (Cohort 1: Phase Ib) II. To determine the pathologic complete response (pCR) rate of neratinib in combination with paclitaxel, pertuzumab, and trastuzumab followed by doxorubicin and cyclophosphamide (AC) in HER2+ metastatic or locally advanced (stage III) inflammatory breast cancer (IBC) patients. (Cohort 1: Phase II) III. To determine the pCR rate of neratinib in combination with paclitaxel followed by AC in HER2-negative/hormone receptor (HR)-positive (HER2-/HR+) metastatic or locally advanced (stage III) IBC patients. (Cohort 2) SECONDARY OBJECTIVES: I. To estimate 2 years progression free survival (PFS) rate of HER2+ metastatic or locally advanced (stage III) IBC patients, and HER2-/HR+ IBC patients treated with neratinib plus anthracycline and taxane based chemotherapy. (Cohort I Phase II and Cohort II) II. To determine toxicity and safety of the combination therapy. EXPLORATORY OBJECTIVES: I. To determine the adaptive target and downstream changes in pan-HER family members induced by one-week window period of neratinib based on tissue and blood based biomarkers. II. To determine the correlation between positive/negative changes in EGFR, HER2 and HER4 and the occurrence of pCR. III. To determine the rate of HER2 mutation in HER2+ IBC and HER2-/HR+ IBC. IV. To determine the association between HER2 mutation and pCR achieved by study combination therapy. V. To determine the correlation between tumor tissue based pharmacodynamic marker changes in association with circulating tumor cells (CTC) and circulating tumor deoxyribonucleic acid (ctDNA). OUTLINE: This is a phase I, dose-escalation study of neratinib followed by a phase II study. Patients are assigned to 1 of 3 groups. GROUP A (COHORT 1 PHASE IB): Patients receive neratinib orally (PO) once daily (QD) on days 1-21, paclitaxel intravenously (IV) over 1-3 hours on days 1, 8, and 15, pertuzumab IV over 1 hour on day 1, and trastuzumab IV over 1-2 hours on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients without progression or excessive toxicity with metastatic disease may receive up to 4 additional courses and with locally advanced disease may receive up to 2 additional courses. GROUP B (COHORT 1 PHASE II): Patients receive neratinib, paclitaxel, pertuzumab, and trastuzumab as in Group A. Patients then receive doxorubicin IV and cyclophosphamide IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery. GROUP C (COHORT 2): Patients receive neratinib PO QD on days 1-21, paclitaxel IV over 1-3 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery/ Patients then receive doxorubicin and cyclophosphamide as in Group B. Patients then undergo standard of care surgery. After completion of study treatment, patients are followed up at 1 month. ;
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