748P - Phase II dose optimization with EZH2/EZH1 inhibitor tulmimetostat in patients with ARID1A-mutated ovarian clear cell carcinoma

Background

Advanced ARID1A-mutated ovarian clear cell carcinoma (OCCC) is a rare disease with poor prognosis that shows limited response to chemotherapy. These patients have not been adequately represented in clinical trials. Oral, next-generation, dual EZH2/EZH1 inhibitor tulmimetostat is in Phase II evaluation in multiple disease cohorts (NCT04104776); we report updated efficacy, safety, and pharmacodynamic findings from the OCCC cohort including new dose optimization arms.

Methods

Phase II Stage 1 evaluated tulmimetostat 350 mg once daily (QD). In Stage 2a (initiation of dose optimization), patients (n=20) with ARID1A-mutated OCCC were randomized 1:1 to either 300 mg or 200 mg QD arms. Observation of ≥2 confirmed complete/partial responses (CR/PR) in each arm in Stage 2a is sufficient per protocol to fully open Stage 2b (plus n=20). Primary endpoint is objective response rate (CR/PR); secondary endpoints include safety.

Results

As of February 18, 2024, 10, 10 and 14 patients with OCCC were enrolled into the 200 mg, 300 mg and 350 mg arms, respectively; 70%, 40% and 57% of patients had received ≥3 prior treatment lines, respectively. Confirmed responses in the OCCC cohort (table) met the criteria for Stage 2b expansion. The safety profile across dose arms was consistent with known class effects. Grade ≥3-related AEs were primarily hematologic (table). Similar pharmacodynamic effects were observed across all three doses as assessed by changes in gene expression. Table: 748P

Response and safety summary in the OCCC cohort ^∗

∗Data cutoff 18-Feb-24.

†RECIST 1.1. CR, complete response; OCCC, ovarian clear cell carcinoma; PD, progressive disease; PR, partial response; SD, stable disease.

Conclusions

This ongoing Phase II data in patients with heavily pretreated ARID1A-mutated OCCC show signs of antitumor activity across dose levels. Response requirements to open Stage 2b have been met in this fast enrolling disease cohort. The safety profile across doses is consistent with EZH2 inhibition. These data support continued investigation of tulmimetostat.

Clinical trial identification

NCT04104776.

Editorial acknowledgement

Medical writing and editorial support for the development of this abstract was provided by Zaavan Baildon of Syneos Health, UK, funded by MorphoSys AG.

Legal entity responsible for the study

Constellation Pharmaceuticals, Inc.

Funding

Constellation Pharmaceuticals, Inc.

Disclosure

A. Oaknin: Financial Interests, Personal, Advisory Board, membership: Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Daiichi Sankyo, Debiopharm International, Eisai, Exelisis, F. Hoffmann-La Roche, Genmab, GSK, ImmunoGen, Itheos, MSD, Mersana Therapeutics, Myriad Genetics, Novocure, OncoXerna Therapeutics, Inc., PharmaMar, Regeneron, Shattuck Labs, Seagen/Pfizer, SutroBiopharma, Zentalis; Financial Interests, Personal, Other, Travel/accomodation: AstraZeneca, PharmaMar, Roche. C. Drescher: Financial Interests, Personal, Leadership Role: Rivkin Center, Powell-Drescher Ovarian Cancer Research Foundation, Swedish Cancer Institute; Financial Interests, Personal, Research Funding: NCI, Canary Foundation. K. Banda: Financial Interests, Personal, Other, Honoraria: GSK, ImmunoGen; Financial Interests, Institutional, Research Funding: Lilly, MorphoSys, Regeneron, Pfizer, Kineta. L. Duska: Financial Interests, Personal, Advisory Role: Regeneron, Inovio Pharmaceuticals; Financial Interests, Institutional, Advisory Role: Merck, Ellipses Pharma, GSK, Millenium, Bristol Myers Squibb, Aeterna Zentaris, Novartis, AbbVie, Tesaro, Cerulean Pharma, Aduro Biotech, Advaxis, Syndax, Pfizer, Genentech/Roche, Morab, Morphotek, Ludwig Institute for Cancer Research; Financial Interests, Personal, Other, Patents, Royalties, Other Intellectual Property: UpToDate, Editor, British Journal of Obstetrics and Gynaecology. V. Ribrag: Financial Interests, Personal, Speaker’s Bureau: AbbVie, BeiGene, Ipsen; Financial Interests, Personal, Research Funding: Astex, GSK; Financial Interests, Personal, Member of Board of Directors: AstraZeneca, Lilly; Financial Interests, Personal, Full or part-time Employment: Pegascy. A. Tewari: Financial Interests, Personal, Advisory Role: Best Doctors, Inc; Financial Interests, Personal, Stocks or ownership: Moderna Therapeutics, Teladoc, B.A.I. Biosciences; Financial Interests, Personal, Other, Honoraria: UroToday. N.J. Lakhani: Financial Interests, Institutional, Research Funding: Alexo Therapeutics, Ascentage Pharma, BeiGene, Constellation Pharmaceuticals, Forty Seven, Loxo, Macrogenics, Merck, Pfizer, Regeneron, Apexian Pharmaceuticals, Coordination Therapeutics, Symphogen, CytomX Therapeutics, InhibRx, Incyte, Jounce Therapeutics, Livzon, Norhern Biologics, Tesaro, Innovent Biologics, LAM Therapeutics, Ikena Oncology, Celgene, Shattuck Labs, Alpine Immune Sciences, Genmab, Odonate Therapeutics, Mersana, Seagen, Astellas Pharma, Celgene, Helsinn Therapeutics, Ikena Oncology, Lilly, Sapience Therapeutics, Epizyme, Gilead Sciences, GSK, Tizona Therapeutics, Inc., Servier, Alkermes, KSQ Therapeutics, Repare Therapeutics, Biosplice, SK Life Sciences, Janssen, Arcus Ventures, Artios, BioNTech, Mural Oncology. L. Eberst: Financial Interests, Personal, Advisory Role: MSD/AstraZeneca, GSK; Financial Interests, Personal, Other, Travel, Accommodations, Expenses.: AstraZeneca. R..D. Harvey: Financial Interests, Personal, Advisory Role: Janssen Oncology, Ribometrix, EMD Serono; Financial Interests, Institutional, Research Funding: Meryx Pharmaceuticals, Janssen Research & Development; Financial Interests, Personal, Research Funding: MorphoSys. L.M. Manso Sanchez: Financial Interests, Personal, Advisory Role: Roche/Genentech, AstraZeneca, Novartis, Pfizer, Tesaro, Eisai, Lilly, Clovis Oncology, Pierre Fabre, GSK; Financial Interests, Personal, Speaker’s Bureau: Roche/Genentech, Novartis, Pfizer, AstraZeneca, Lilly; Financial Interests, Personal, Research Funding: Tesaro; Financial Interests, Personal, Other, Travel, Accommodations, Expenses.: Roche/Genentech, Novartis, Tesaro, MSD Oncology, GSK. D. Lorusso: Financial Interests, Personal, Advisory Board, Participation in advisory boards: AstraZeneca, Clovis Oncology, GSK, MSD; Financial Interests, Personal, Advisory Board, also invited member: Corcept, Genmab, ImmunoGen, Oncoinvest, Seagen, Sutro; Financial Interests, Personal, Advisory Board: Novocure; Financial Interests, Personal, Other, Consultancy: MSD, Novartis; Financial Interests, Personal, Invited Speaker, for advisory board: AstraZeneca, Clovis Oncology, Daiichi Sankyo, Genmab, GSK, ImmunoGen, MSD, Novocure, Seagen; Financial Interests, Institutional, Funding, Clinical trial/contracted research: AstraZeneca, Clovis Oncology; Financial Interests, Institutional, Funding, grant for founding academic trials: Clovis Oncology, Pharmaand, GSK, MSD; Financial Interests, Institutional, Funding, Clinical trials/contracted research: Genmab, GSK, ImmunoGen, Incyte, MSD, Novartis, Roche, Seagen, Alkermes, Corcept; Non-Financial Interests, Personal, Principal Investigator, PI of several trials. No personal compensation received: AstraZeneca, Clovis Oncology, Genmab, GSK, Incyte, MSD; Non-Financial Interests, Personal, Principal Investigator, PI of clinical trial. No personal compensation received: ImmunoGen, Novartis, Roche, Seagen, Corcept; Non-Financial Interests, Personal, Principal Investigator, PI of clinical trials. No personal compensation received: PharmaMar; Non-Financial Interests, Personal, Member of Board of Directors: GCIG; Non-Financial Interests, Personal, Member, President Elect: MITO; Non-Financial Interests, Personal, Member, Coordinating PI of several trials: ENGOT; Other, Personal, Other, Grants for travelling: AstraZeneca, Menarini, GSK, MSD. H.S. Walter: Financial Interests, Personal, Other, Honoraria: BeiGene, Genmab, Loxo, AstraZeneca; Financial Interests, Personal, Advisory Role: Genmab, BeiGene, Loxo; Financial Interests, Personal, Research Funding: Gilead Sciences, Pfizer. D.G. Illescas: Financial Interests, Personal, Speaker’s Bureau: GSK, AstraZeneca; Financial Interests, Personal, Other, Travel and accommodation fees: GSK, MSD; Financial Interests, Personal, Speaker’s Bureau, Travel and accommodation fees: AstraZeneca. E. Pons-Tostivint: Financial Interests, Personal, Advisory Role: AstraZeneca, Sanofi Pasteur, Takeda; Financial Interests, Personal, Other, Travel, accommodations, expenses: AstraZeneca, Takeda, Pfizer, Sanofi. A.G. Thakur, L. Kann, A. Reddy, N. Faulhaber: Financial Interests, Personal, Full or part-time Employment: MorphoSys. A. González-Martín: Financial Interests, Personal, Advisory Role: Roche, Tesaro/GSK, Clovis Oncology, AstraZeneca, MSD, Genmab, ImmunoGen, Oncoinvent, Pfizer/EMD Serono, Amgen, Mersana, SOTIO, Sutro Biopharma, Macrogenics, Novartis, Alkermes, Hedera Dx, Novocure, Seagen, Takeda, Kartos Therapeutics, Tubulis GmbH; Financial Interests, Personal, Speaker’s Bureau: Roche, AstraZeneca, Tesaro/GSK, PharmaMar, Clovis Oncology, MSD Oncology; Financial Interests, Personal, Other, Travel/ Accommodations, Expenses.: Roche, AstraZeneca, PharmaMar, Tesaro/GSK, MSD Oncology; Financial Interests, Institutional, Research Funding: Roche, Tesaro/GSK. All other authors have declared no conflicts of interest.