TPS255 Background: The histone methyltransferase EZH2 is overexpressed in many cancers. In prostate cancer (PC), EZH2 inhibition may reverse acquired resistance to androgen inhibitors (AIs). Pts may initially respond to AIs, but pts who progress have limited treatment options. In phase 2 trials, TAZ, a selective, orally bioavailable, investigative small molecule EZH2 inhibitor, has demonstrated encouraging objective responses in B-cell lymphomas and molecularly defined solid tumors and a favorable safety profile. In PC preclinical models, TAZ + E or A/P showed a greater reduction in tumor growth than either drug alone. This study will evaluate the safety and efficacy of TAZ + E or A/P vs E or A/P alone in mCRPC. Methods: This phase 1b/2 study will enroll pts ≥18 years with progressive mCRPC, with or without prior second-generation AI treatment, and no prior chemotherapy. Phase 1b will identify the recommended phase 2 dose (RP2D) of TAZ when combined with E (160 mg/day) or A/P (A: 1000 mg/day; P: 5 mg twice-daily [BID]) and evaluate the safety and tolerability of each combination in treatment-naïve pts and pts previously treated with a second-generation AI. Using a modified 3+3 design (up to 48 pts: 18 for TAZ+A/P and 30 for TAZ+E), TAZ dosing will start at 400 mg BID, escalating to 800 mg BID in the TAZ+A/P group or 1600 mg BID in the TAZ + E group, if no dose-limiting toxicities are observed. Phase 2 will begin once the RP2D for each combination is determined. Efficacy and safety results from phase 1b will inform the final design for phase 2. Phase 2 will be an open label study where pts will be randomized to either E or A/P alone or in combination with TAZ. TAZ will be administered at the RP2D in continuous 28-day cycles for as long as pts tolerate treatment and continue AI therapy. Tumor assessments will be performed every 9 weeks for 6 months and every 12 weeks thereafter. Efficacy assessments include radiographic progression-free survival (primary endpoint), prostate-specific antigen (PSA) ≥50% response rate, time to PSA progression, time to subsequent systemic therapy, and objective response rate. Safety is a secondary endpoint.
SECOND GENERATION PFBC SYSTEMS R AND D - PHASE 2 AND 3