GDC-0941 and Cisplatin in Treating Patients With Androgen Receptor-Negative Triple Negative Metastatic Breast Cancer

PRIMARY OBJECTIVES: I. To determine the safety and tolerability of GDC-0941 when given in combination with cisplatin in patients with androgen receptor-negative (AR-) triple negative (TN) metastatic breast cancer (MBC): assessment of dose limiting toxicities (DLTs) during the first 4 weeks of treatment (cycle 1); determination of the maximally tolerated dose (MTD) and recommended phase II dose of GDC-0941 given in combination with cisplatin. (Phase IB) II. To evaluate the efficacy, as measured by the overall response rate (ORR), of cisplatin + GDC-0941 versus cisplatin alone in patients with AR- TN MBC. (Phase II) SECONDARY OBJECTIVES: I. To determine the clinical benefit rate (CBR) of cisplatin + GDC-0941 in patients with AR- TN MBC. II. To determine the time to disease progression (TTP) of cisplatin + GDC-0941 versus cisplatin alone in patients with AR- TN MBC. TERTIARY OBJECTIVES: I. To characterize pharmacokinetics of GDC-0941 when administered in combination with cisplatin. II. To explore predictors of response and mechanisms of resistance based on exploratory analysis of tumor tissue obtained through biopsies. III. To assess the prognostic effects of phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations and phosphatase and tensin homolog (PTEN) loss on TTP and CBR. OUTLINE: This is a phase I, dose-deescalation study of PI3K inhibitor GDC-0941 followed by a randomized phase II study. PHASE I: Patients receive cisplatin intravenously (IV) over 1 hour on days 1, 8, and 15 and PI3K inhibitor GDC-0941 orally (PO) once daily (QD) on days 2-6, 9-13, 16-20, and 23-27. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive cisplatin IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may crossover to Arm II upon disease progression. ARM II: Patients receive cisplatin as in Arm I and PI3K inhibitor GDC-0941 PO QD on days 2-6, 9-13, 16-20, and 23-27. 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.