LEE011 (Ribociclib) in Combination With Docetaxel Plus Prednisone in mCRPC

PRIMARY OBJECTIVES: I. To determine the safety profile, maximally tolerated dose (MTD), and recommended phase 2 dose of ribociclib in combination with docetaxel plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC). (Phase IB) II. To determine the 6-month radiographic progression-free survival rate with the combination of ribociclib, docetaxel, and prednisone in patients with mCRPC. (Phase 2) SECONDARY OBJECTIVES: I. To determine the median radiographic progression-free survival with the combination of ribociclib, docetaxel, and prednisone in patients with mCRPC. II. To determine the objective response rate and median duration of response among patients with measurable disease at baseline. III. To determine the prostate-specific antigen (PSA) response proportion and time to PSA progression. IV. To characterize the safety profile of ribociclib in combination with docetaxel. V. To determine if there is evidence of drug-drug interaction between docetaxel + prednisone with ribociclib. EXPLORATORY OBJECTIVES: I. To determine whether baseline or percent change from baseline in gallium citrate uptake on positron emission tomography (PET) scan is associated with clinical outcomes. (For University of California San Francisco (USCF) Patients Only) II. To determine whether genomic assessment of MYC pathway activation (MYC amplification or overexpression, Rb1 deletion, cyclin D/E and CDK 4/6 overexpression) assessed within metastatic tumor tissue, circulating tumor cells (CTCs), and/or cell-free circulating tumor deoxyribonucleic acid (ctDNA) is predictive of clinical outcomes with the combination of ribociclib plus docetaxel. III. To determine whether MYC activation score as determined by validated expression signature can distinguish those with and without clinical benefit with ribociclib in combination with docetaxel. IV. To use an unbiased approach with integration of clinical, genomic, and proteomic data (differential pathway signature correlation; DiPSC) to define a signature associated with response to taxane + CDK4/6 inhibition in mCRPC. OUTLINE: This is a phase Ib, dose-escalation study of ribociclib followed by a phase II study. Patients receive docetaxel intravenously (IV) over 1 hour on day 1 or on days 1 and 8, prednisone orally (PO) twice daily (BID) on days 1-21, and ribociclib PO once daily (QD) on days 1-4, and 8-15. Treatment repeats every 21 days for 9 cycles in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or better on re-staging scans after 6 cycles and patients without radiographic or clinical disease progression after 9 cycles of treatment may continue on single agent maintenance ribociclib PO QD on days 1-14 of every 21 day cycle in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every three months.