Abstract 1870TiP
Background
Overexpression or amplification of enhancer of zeste homolog 2 (EZH2) is described in many tumor types, including small cell lung cancer (SCLC), prostate cancer, and ovarian cancer (OVCA). EZH2 inhibition augmented PARP inhibitor (PARPi) activity in OVCA and metastatic castration-resistant prostate cancer (mCRPC) cell lines and tumors, some of which are resistant to PARPis. EZH2 inhibitor (EZH2i) and PARPi in combination also demonstrated synergy in chemotherapy-resistant SCLC cell lines and tumors. EZH2 inhibition has been shown to modify the tumor microenvironment to enhance immune checkpoint blockade, supporting EZH2 and immune checkpoint inhibition in SCLC. Tazemetostat is an EZH2i approved for treatment of epithelioid sarcoma and relapsed/refractory follicular lymphoma. Given the preclinical data and favorable tolerability of tazemetostat, we examine tazemetostat’s safety and efficacy in combination with a PARPi or checkpoint inhibitor (CPI).
Trial design
This is a 2-part, multicenter, open-label, phase 1b/2 trial of tazemetostat + PARPi in pts with PARPi-resistant mCRPC, OVCA, or SCLC, or tazemetostat + CPI maintenance in pts with extensive-stage SCLC. Eligible pts are adults with ECOG performance status of 0–1 and measurable disease by RECIST v1.1 (for pts with SCLC or OVCA) or PCWG3 (for pts with mCRPC). The dose escalation phase 1b segment will assess the safety and tolerability of tazemetostat + PARPi in pts with mCRPC, OVCA, or SCLC and tazemetostat + CPI in pts with SCLC. It will determine the recommended phase 2 dose (RP2D) of tazemetostat, starting at 800 mg twice daily (BID), based on dose-limiting toxicities and pharmacokinetics. The phase 2 segment will evaluate the efficacy and safety of tazemetostat + PARPi and tazemetostat + CPI at the RP2D. The primary efficacy endpoint for each cohort in phase 2 is the objective response rate (ORR) per RECIST 1.1 for the PARPi combinations and progression-free survival (PFS) for the CPI combination. Secondary endpoints include PFS for PARPi combinations, ORR for the CPI combination, and duration of response, overall survival, and disease control rate for all combinations.
Clinical trial identification
Editorial acknowledgement
Claire Jarvis, PhD and Duprane Young, PhD, of Peloton Advantage, an OPEN Health company, and funded by Epizyme, Inc.
Legal entity responsible for the study
Epizyme, Inc.
Funding
Epizyme, Inc.
Disclosure
C.M. Rudin: Financial Interests, Personal and Institutional, Stocks/Shares: Earli; Financial Interests, Personal and Institutional, Funding: Merck; Financial Interests, Personal and Institutional, Funding: Daiichi Sankyo; Financial Interests, Personal and Institutional, Funding: Roche; Financial Interests, Personal and Institutional, Advisory Role: Harpoon Therapeutics; Financial Interests, Personal and Institutional, Advisory Role: Bridge Medicines; Financial Interests, Personal and Institutional, Advisory Role: Amgen; Financial Interests, Personal and Institutional, Advisory Role: AbbVie; Financial Interests, Personal and Institutional, Advisory Role: Genentech; Financial Interests, Personal and Institutional, Advisory Role: Epizyme, Inc.; Financial Interests, Personal and Institutional, Advisory Role: Ispen; Financial Interests, Personal and Institutional, Advisory Role: Jazz; Financial Interests, Personal and Institutional, Advisory Role: Merck Syros. W. Abida: Financial Interests, Personal and Institutional, Other, Honoraria: CARET; Financial Interests, Personal and Institutional, Advisory Role: Clovis Oncology; Financial Interests, Personal and Institutional, Advisory Role: Janssen; Financial Interests, Personal and Institutional, Advisory Role: MORE Health; Financial Interests, Personal and Institutional, Advisory Role: ORIC Pharmaceuticals; Financial Interests, Personal and Institutional, Funding: AstraZeneca (Inst); Financial Interests, Personal and Institutional, Funding: Clovis Oncology (Inst); Financial Interests, Personal and Institutional, Funding: GlaxoSmithKline (Inst); Financial Interests, Personal and Institutional, Funding: Zenith Epigenetics (Inst); Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses : Clovis Oncologs; Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses : GlaxoSmithKline; Financial Interests, Personal and Institutional, Other, Travel: ORIC Pharmaceuticals. A. Spira: Financial Interests, Personal and Institutional, Stocks/Shares: Lilly; Financial Interests, Personal and Institutional, Other, Honoraria: AstraZeneca/MedImmune; Financial Interests, Personal and Institutional, Other, Honoraria: CytomX Therapeutics; Financial Interests, Personal and Institutional, Other, Honoraria: Merck; Financial Interests, Personal and Institutional, Advisory Role: Amgen; Financial Interests, Personal and Institutional, Advisory Role: Array BioPharma (Inst); Financial Interests, Personal and Institutional, Advisory Role: incyte; Financial Interests, Personal and Institutional, Advisory Role: Novartis; Financial Interests, Personal and Institutional, Funding: Abbvie (Inst); Financial Interests, Personal and Institutional, Funding: Arch Therapeutics (Inst); Financial Interests, Personal and Institutional, Funding: Astellas Pharma (Inst); Financial Interests, Personal and Institutional, Funding: Astex Pharmaceuticals (Inst); Financial Interests, Personal and Institutional, Funding: AstraZeneca (Inst); Financial Interests, Personal and Institutional, Funding: Boehringer Ingelheim (Inst); Financial Interests, Personal and Institutional, Funding: Bristol-Myers Squibb (Inst); Financial Interests, Personal and Institutional, Funding: CytomX Therapeutics (Inst); Financial Interests, Personal and Institutional, Funding: Gritstone Oncology (Inst); Financial Interests, Personal and Institutional, Funding: Ignyta (Inst); Financial Interests, Personal and Institutional, Funding: Incyte (Inst); Financial Interests, Personal and Institutional, Funding: LAM Therapeutics; Financial Interests, Personal and Institutional, Funding: LAM Therapeutics (Inst); Financial Interests, Personal and Institutional, Funding: Loxo (Inst); Financial Interests, Personal and Institutional, Funding: Macrogenics (Inst); Financial Interests, Personal and Institutional, Funding: MedImmune (aInst); Financial Interests, Personal and Institutional, Funding: Newlink Genetics (Inst); Financial Interests, Personal and Institutional, Funding: Novartis (Inst); Financial Interests, Personal and Institutional, Funding: Roche (Inst); Financial Interests, Personal and Institutional, Funding: Takeda (Inst); Financial Interests, Personal and Institutional, Funding: Trovagene (Inst). R. Chadha: Financial Interests, Personal and Institutional, Stocks/Shares: Epizyme, Inc.; Financial Interests, Personal and Institutional, Full or part-time Employment: Epizyme, Inc. J. Yang: Financial Interests, Personal and Institutional, Stocks/Shares: Epizyme, Inc.; Financial Interests, Personal and Institutional, Full or part-time Employment: Epizyme, Inc. D. Powers: Financial Interests, Personal and Institutional, Stocks/Shares: Epizyme, Inc.; Financial Interests, Personal and Institutional, Full or part-time Employment: Epizyme, Inc. R. Coleman: Financial Interests, Personal and Institutional, Advisory Role: Clovis Oncology; Financial Interests, Personal and Institutional, Advisory Role: DOD-CDRMP; Financial Interests, Personal and Institutional, Advisory Role: Esperance Pharmaceuticals; Financial Interests, Personal and Institutional, Advisory Role: Genentech/Roche; Financial Interests, Personal and Institutional, Advisory Role: NCCN; Financial Interests, Personal and Institutional, Funding: Abbott/AbbVie; Financial Interests, Personal and Institutional, Funding: Array BioPharma; Financial Interests, Personal and Institutional, Funding: AstraZeneca/MedImmune; Financial Interests, Personal and Institutional, Funding: Clovis Oncology; Financial Interests, Personal and Institutional, Funding: Esperance Pharmaceuticals; Financial Interests, Personal and Institutional, Funding: Johnson & Johnson; Financial Interests, Personal and Institutional, Funding: Merck; Financial Interests, Personal and Institutional, Funding: OncoMed; Financial Interests, Personal and Institutional, Funding: Roche/Genentech; Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses : Amgen; Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses : Array BioPharma; Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses : AstraZeneca/MedImmune; Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses : Bayer; Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses : Clovis Oncology; Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses : GOG; Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses : Merck; Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses : Millennium; Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses : New Mexico Cancer Center; Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses : Research to Practice; Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses : Roche/Genentech; Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses : University of California; Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses : Irvine; Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses : University of Cincinnati Cancer Center; Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses : University of Miami.