Taselisib and Enzalutamide in Treating Patients With Androgen Receptor Positive Triple-Negative Metastatic Breast Cancer

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PRIMARY OBJECTIVES: I. To determine the safety and tolerability of taselisib given in combination with enzalutamide: Assessment of dose limiting toxicities (DLTs) during the first 4 weeks of treatment (cycle 1). (Phase Ib) II. To determine the safety and tolerability of taselisib given in combinatio...

PRIMARY OBJECTIVES: I. To determine the safety and tolerability of taselisib given in combination with enzalutamide: Assessment of dose limiting toxicities (DLTs) during the first 4 weeks of treatment (cycle 1). (Phase Ib) II. To determine the safety and tolerability of taselisib given in combination with enzalutamide: Determination of the maximally tolerated dose (MTD) of taselisib given in combination with enzalutamide. (Phase Ib) III. To evaluate the efficacy, as measured by clinical benefit rate (CBR), of enzalutamide + taselisib in patients with androgen receptor positive (AR+) triple negative (TN) metastatic breast cancer (MBC). (Phase II) SECONDARY OBJECTIVES: I. To determine the progression free survival (PFS) of enzalutamide + taselisib in patients with AR+ TN MBC. II. To assess the pharmacokinetics (PKs) of taselisib and enzalutamide in patients with AR+ TN MBC. TERTIARY OBJECTIVES: I. To explore predictors of biomarker response and mechanisms of resistance based on exploratory analysis of tumor tissue obtained through biopsies. II. Levels of phosphatase and tensin homolog (PTEN) expression by immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qPCR). III. Presence of mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene. IV. Human epidermal growth factor receptor 2 (HER2) (IHC, fluorescence in situ hybridization [FISH]) and estrogen receptor (ER)/progesterone receptor (PR) levels (IHC) in tumor biopsy from a metastatic site. V. Levels of mitogen-activated protein kinase kinase (MEK) activity measured by phosphorylated extracellular-signal-regulated kinases (p-ERK1/2) (IHC) and phosphorylated p-ribosomal protein S6 (S6) (S235/236 and S240/244) at baseline and upon progression of disease. VI. Levels of phosphorylated v-akt murine thymoma viral oncogene homolog 1 (p-AKT) (IHC) at baseline and upon progression of disease. VII. Gene expression profiling to assign a triple negative subtype. VIII. Whole exome deoxyribonucleic acid (DNA)-sequencing (seq) on DNA isolated at baseline and upon progression. IX. Plasma for circulating tumor DNA (ctDNA) analysis to assess PIK3CA mutation status in response and resistance. X. To assess the predictive effects of PIK3CA mutations and PTEN loss on PFS and CBR. XI. To evaluate the ability of multi-parametric magnetic resonance imaging (MRI) performed early in therapy to predict both biological and clinical response. OUTLINE: This is a phase Ib, dose-escalation study of taselisib followed by a randomized phase II study. PHASE IB: Patients receive taselisib orally (PO) once daily (QD) on days 1-28 and enzalutamide PO QD on days 9-28 of course 1 and days 1-28 of subsequent courses. 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 taselisib PO QD and enzalutamide as in Phase Ib. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing unacceptable toxicity due to enzalutamide may continue to receive taselisib. ARM II: Patients receive enzalutamide PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients may crossover to Arm I. After completion of study treatment, patients are followed up for 30 days and then every 3 months for 3 years.

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