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

Prostate Cancer Clinical Trial

Official title: A Phase 1b/2 Study of the Oral CDK4/6 Inhibitor LEE011 (Ribociclib) in Combination With Docetaxel Plus Prednisone in Metastatic Castration Resistant Prostate Cancer

Status Completed

Clinical Trial Summary

This is a Phase Ib/II open label clinical trial in patients with metastatic castration resistant prostate cancer. The objective of the phase Ib portion of the study is to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of docetaxel (75 mg/m2 IV q21 days) and prednisone (5mg orally BID) in combination with ribociclib in escalating oral daily doses in patients with metastatic castrate resistant prostate cancer (mCRPC) with prior resistance to abiraterone and/or enzalutamide who have not undergone prior chemotherapy for metastatic disease. Up to three cohorts will be enrolled to determine the MTD and DLT profile of this combination during Phase 1b. Dose escalation will follow the standard 3+3 design. The dosing schedule is being chosen to allow patients to be exposed to the most efficacious dosing schedule of docetaxel (75 mg/m2 every 3 weeks). If there is excess toxicity observed with the treatment combination at the first dose level (dose level I), an alternative dosing schema may be pursued with weekly docetaxel treatment (35 mg/m2 weekly), which has demonstrated activity in mCRPC and decreased risk of cytopenias compared with every 3 week dosing schedule. The Phase II portion (N = 29) of the study is a single arm, two stage, open-label study of ribociclib (dosed at the RP2D) in combination with docetaxel and prednisone to determine the efficacy and further define the safety of the treatment combination. Patients will be treated with the combination of ribociclib plus docetaxel + prednisone for up to 9 cycles. If there is no evidence of radiographic or clinical disease progression after 9 cycles of protocol therapy, patients may continue on single agent maintenance ribociclib until the time of disease progression. Patients will have the option of starting maintenance ribociclib after 6 cycles of docetaxel if stable disease or better on re-staging scans. The dose of ribociclib used during maintenance will be the same dose as that immediately preceding cessation of docetaxel treatment.

Clinical Trial Description

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. ;

Related Conditions & MeSH terms

• Prostate Cancer
• Prostatic Neoplasms

• NCT number: NCT02494921
• Study type: Interventional
• Source: University of California, San Francisco
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: November 20, 2015
• Completion date: July 30, 2021