ProSTAR: A phase Ib/II study of CPI-1205, a small molecule inhibitor of EZH2, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration-resistant prostate cancer (mCRPC).

Abstract

TPS335 Background: EZH2 is frequently mutated and/or overexpressed in numerous cancers. High EZH2 expression is correlated with poor outcomes in prostate cancer patients (Varambally, 2002). EZH2 inhibition combines synergistically with anti-androgen therapies in preclinical models of advanced prostate cancer, suggesting epigenetic reprogramming as a pathophysiologic mechanism to enhance the combination therapy (Ku, 2017; Xiao 2018; Constellation, unpublished). CPI-1205 is a potent, selective, and cofactor-competitive inhibitor of wild type and mutant EZH2 catalytic activity, which demonstrates anti-proliferative effects in prostate and other cancer cell models. Methods: We present a Phase 1b/2 multicenter study of CPI-1205 combined with either E or A/P in patients with mCRPC, which includes phase 1 dose escalation, an expansion cohort in heavily pretreated patients (HPEC), and a randomized phase 2 study. Key eligibility criteria include progressive mCRPC in patients previously treated with a second-generation androgen inhibitor, ECOG 0-1, and measurable or non-measurable disease. During the phase 1b, patients will receive CPI-1205 continuously in 28-day cycles combined with the standard dose of either E (160mg PO once daily) or A/P (1000mg PO once daily/5 mg BID). The primary objective in Phase 1b is to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of CPI-1205 combined with either E or A/P. Secondary objectives include safety, pharmacokinetic and pharmacodynamic profiles, and anti-tumor activity. The HPEC arm, with Simon’s 2-stage design, may begin with the regimen that is deemed safe by the study safety committee. The primary endpoint of the HPEC arm is objective response rate (ORR) per PCWG3, with a requirement ≥ 1 measurable lymph node at baseline. Once RP2D is established, we will start a randomized Phase 2 trial of E or A/P combined with CPI-1205 vs. E or A/P alone. The co-primary endpoint includes PSA50 and composite response rate (either CTC 30% reduction or ORR per PCWG3). Patient accrual in US sites began in December 2017. Clinical trial information: NCT03480646.