Multicenter, phase I/II trial of anastrozole,palbociclib, trastuzumab, and pertuzumab in HR-positive,HER2-positive metastatic breast cancer

Background: Overexpression or amplification of HER2 occurs in approximately 15-20% of patients and roughly half of these tumors are hormone receptor (HR) positive. The use of aromatase inhibitors in the metastatic setting is wellestablished while significant improvement in overall survival has been established with the use of trastuzumab orpertuzumab in HER2-overexpressing tumors. This study will examine the combination of endocrine therapy,palbociclib, and dual HER2 therapy with pertuzumab and trastuzumab in women with metastatic HR+, HER2+breast cancer. Trial Design: Multicenter, phase I/II trial of Anastrozole, Palbociclib, Trastuzumab and Pertuzumab inHR+, Her2+ metastatic breast cancer. Eligibility Criteria: Newly diagnosed stage IV HR+, HER2+ breast cancerpatients. Specific Aims: Phase I: To determine the maximum dose tolerated of palbociclib. Phase II: To determine the clinical benefit rate (CBR) of treatment with anastrozole, palbociclib, trastuzumab, and pertuzumab in HR+,HER2+ metastatic breast cancer patients. Exploratory: Examine potential biomarkers of response to palbociclibincluding expression of cyclin D1, cyclin E1 and E2, CDK 2, CDK 4, CDK 6, retinoblastoma, phosphorylatedretinoblastoma, and p16. RNA sequencing will be used to assess for other predictors of response in an unbiasedmanner to assess for correlation with inhibition of Ki-67 and phosphorylated retinoblastoma expression as well asevaluate for potential mechanisms of resistance. Methods: This study will evaluate the maximum tolerated dose(MTD) of the Anastrozole, Palbociclib, Trastuzumab and Pertuzumab. Once the MTD is reached, we will assess theclinical benefit rate using a Simon's II stage design among a maximum 30 patients. Accrual: Maximum of 36subjects. Current Enrollment: Enrollment to phase I ended in October 2018 with one dose escalation to palbociclib125mg, at which level one DLT was observed. Thus, the MTD was determined at palbociclib 125 mg and subsequent phase II patients will be treated at this dose level. Enrollment to phase II began in February 2019. 39%of planned patients have been enrolled as of January 2020.