Ribociclib, Tucatinib, and Trastuzumab for the Treatment of HER2 Positive Breast Cancer

PRIMARY OBJECTIVES: I. To assess the safety of the combination of ribociclib, tucatinib, and trastuzumab in patients with metastatic, HER2+ breast cancer. (Phase 1 Dose Escalation Trial) II. To determine the recommended phase 2 dose of ribociclib when combined with tucatinib and trastuzumab. (Phase 1 Dose Escalation Trial) III. To assess the pathologic complete response (pCR). (Phase 2 Neoadjuvant Study) SECONDARY OBJECTIVES: I. To evaluate the pharmacokinetics of ribociclib and tucatinib when given in combination. (Phase 1 Dose Escalation Trial) II. To assess the clinical objective response rate after 3 cycles via Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. (Phase 1 Dose Escalation Trial) III. To assess the clinical objective response rate in the experimental arms. (Phase 2 Neoadjuvant Study) IV. To assess quality of life by evaluating toxicity burden using a quality of life (QOL)/patient-reported outcomes (PRO) questionnaire- the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (EORTC QLQ-C30) instrument. (Phase 2 Neoadjuvant Study) V. To assess the molecular changes in tumor biomarkers after 1 cycle of targeted therapy (anti-HER2, anti-estrogen, and CDK 4/6 directed therapy). (Phase 2 Neoadjuvant Study) VI. Pathological Assessment According to Residual Cancer Burden (RCB) Index at surgery. (Phase 2 Neoadjuvant Study) EXPLORATORY OBJECTIVE: I. To investigate potential serum and tumor predictive biomarkers to predict response to experimental therapy. (Phase 2 Neoadjuvant Study) OUTLINE: This is a phase Ib, dose-escalation study of ribociclib followed by a phase II study. PHASE Ib: Patients receive ribociclib orally (PO) once daily (QD) on days 1-21, tucatinib PO twice daily (BID) on days 1-28, and trastuzumab intravenously (IV) over 30-90 minutes every 7 days. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. PHASE II: Patients with hormone receptor (HR) positive status are randomized to Arm A or Arm B. Patients with HR negative status are randomized to Arm B or Arm C. ARM A: Patients receive ribociclib PO QD on days 1-21, tucatinib BID on days 1-28, trastuzumab IV over 30-90 minutes every 7 days and fulvestrant subcutaneously (SC) on days 1 and 15 of cycle 1 and day 1 of every subsequent cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive docetaxel IV over 1 hour on day 1, carboplatin IV on day 1, trastuzumab IV over 30-90 minutes on day 1, and pertuzumab IV over 1 hour on day 1. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. ARM C: Patients receive ribociclib PO QD on days 1-21, tucatinib BID on days 1-28, and trastuzumab IV over 30-90 minutes every 7 days. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed-up within 7 and 30 days.