Abstract 492TiP
Background
Methylthioadenosine phosphorylase (MTAP) deletion occurs in ∼15% of solid tumors in the setting of 9p21 loss and is associated with poor survival (Nature Communications; 2021; 12:5606; Han G). Loss of MTAP results in methylthioadenosine (MTA) accumulation and partial inhibition of protein arginine methyltransferase-5 (PRMT5). Inhibition of methionine adenosyltransferase-2a (MAT2A) results in reduction of s-adenosyl methionine (SAM), starving PRMT5 of its methylation substrate with resulting selective sensitivity of MTAP null cancer cells. IDE397 is a novel MAT2A inhibitor being evaluated in cancer patients harboring a tumor having MTAP deletion. IDE397 has superior cellular potency, selectivity, and drug properties, including lack of liver toxicity signals and high solubility, compared to the other MAT2A inhibitors under clinical investigation. In preclinical models, including patient derived xenografts, IDE397 has been shown to exploit the synthetic lethal relationship between MTAP deletion and MAT2A with broad activity and regressions of tumors with MTAP loss as a single agent and in combination with taxanes and other chemotherapy agents across multiple solid tumor indications. Preclinically, IDE397 shows robust pharmacodynamic modulation of SAM and symmetric dimethylarginine (SDMA). (IDEAYA Data).
Trial design
Study IDE397-001 (NCT04794699), is a phase I, muticenter, open-label study of IDE397 as a single agent in adult participants with advanced solid tumors harboring MTAP deletion. Additional escalation, expansion and combination arms with taxanes and other agents are planned across multiple indications (NSCLC, esophagogastric and other solid tumors). All participants will receive oral daily dosing of IDE397, as monotherapy or in combination with chemotherapy, until disease progression, unacceptable toxicity, or other withdrawal criteria are met. Primary endpoints include safety and tolerability, RP2D determination, investigator-assessed tumor response by RECIST v1.1. Enrollment in the monotherapy dose escalation is ongoing with clearance of the first 5 dose levels without DLT.
Clinical trial identification
NCT04794699.
Editorial acknowledgement
Legal entity responsible for the study
IDEAYA Biosciences, Inc.
Funding
IDEAYA Biosciences.
Disclosure
M.L. Johnson: Financial Interests, Institutional, Advisory Role: Genentech/Roche, Boehringer Ingelheim, AstraZeneca, Calithera Biosciences, Merck, Sanofi, Mirati Therapeutics, Ribon Therapeutics, AbbVie, GlaxoSmithKline, Gritstone Bio, Janssen Oncology, Lilly, Amgen, Bristol-Myers Squibb, Daiichi Sankyo, EMD Serono, G1 Therapeutics, WindMIL, Eisai, Axelia Oncology, Black Diamond Therapeutics, CytomX Therapeutics, EcoR1 Capital, Editas Medicine, Genmab, IDEAYA Biosciences, ITeos Therapeutics, Oncorus, Regeneron, Turning Point Therapeutics, Astellas Pharma; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AbbVie, AstraZeneca, Genentech, Incyte, Merck, Pfizer, Sanofi; Financial Interests, Institutional, Funding: EMD Serono, Kadmon, Janssen, Mirati, Genmab, Pfizer, AstraZeneca, Stem CentRx, Novartis, Checkpoint Therapeutics, Array BioPharma, Regeneron, Merck, Hengrui Pharmaceutical, Lycera, BeiGene, Tarveda Therapeutics, Loxo, AbbVie, Boehringer Ingelheim, Guardant Health, Daiichi Sankyo, Sanofi, CytomX Therapeutics, Dynavax Technologies, Corvus Pharmaceuticals, Incyte, Genocea Biosciences, Gritstone Bio, Amgen, Genentech/Roche, Adaptimmune, Syndax, Neovia Oncology, Acerta Pharma, Takeda, Shattuck Labs, GlaxoSmithKline, Apexigen, Atreca, OncoMed, Lilly, Immunocore, Jounce Therapeutics, University of Michigan, WindMIL, TCR2 Therapeutics, Arcus Biosciences, Ribon Therapeutics, BerGenBio, Calithera Biosciences, Tmunity Therapeutics, Inc., Seven and Eight Biopharmaceuticals, Rubius Therapeutics, Curis, Silicon Therapeutics, Dracen, PMV Pharma, Artios, BioAtla, Elicio Therapeutics, Erasca, Inc, Harpoon, Helsinn Healthcare, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Memorial Sloan-Kettering Cancer Center, NeoImmuneTech, Numab, RasCal, Relay Therapeutics, Revolution Medicine, Tempest Therapeutics, Tizona Therapeutics, Inc., Turning Point Therapeutics, Vyriad, Y-mAbs Therapeutics, Exelixis, Fate Therapeutics, Merus, Black Diamond Therapeutics, Kartos Therapeutics, Carisma Therapeutics, Rain Therapeutics, Nuvalent, Inc., Palleon Pharmaceuticals, Impact Therapeutics. J. Rodon: Financial Interests, Personal, Advisory Board: Peptomyc, Kelun Pharmaceuticals/Klus Pharma, Ellipses Pharma, Molecular Partners, IONCTURA SA; Financial Interests, Institutional, Other, Clinical Research: Bayer, Novartis, Spectrum Pharmaceuticals, Symphogen, BioAlta, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GlaxoSmithKline; Financial Interests, Institutional, Other, Research Funding: Blueprint Medicines, Black Diamond, Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant, Research Funding/Clinical Research: Hummingbird, Yingli; Financial Interests, Institutional, Research Grant, Research Funding: Vall d'Hebron Institute of Oncology/Cancer Core Europe; Financial Interests, Institutional, Research Grant, Clinical Research: Bicycle Therapeutics, Taiho, Roche Pharmaceuticals, Merus, Curis, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Hutchinson MediPharma, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics; Other, Other: VHIO/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, Boxer Capital, LLC, Tang Advisors, LLC; Other, Travel Reimbursement: European Society for Medical Oncology. R. Aljumaily: Financial Interests, Institutional, Funding: Regeneron, AstraZeneca, Alliance Foundation Trials, Boston Biomedical, Syneos Health, Array BioPharma, Bristol-Myers Squibb, Huntsman Cancer Institute, Merck, AstraZeneca, AbbVie, Regeneron, G1 Therapeutics, Roche, Genentech, MedImmune, GlaxoSmithKline, Novartis, Peloton Therapeutics, Baxalta, Lilly, EMD Serono, Boehringer Ingelheim, Tesaro, Pfizer, Checkpoint Therapeutics, Bicycle Therapeutics, Bioinvent, Immunocore, ImmunoGen, Xencor, IDEAYA Biosciences. M. Villalona-Calero: Financial Interests, Personal, Invited Speaker, speaker bureau: Amgen; Financial Interests, Personal, Stocks/Shares: Moderna; Financial Interests, Institutional, Invited Speaker, local PI clinical trial: Amgen; Financial Interests, Institutional, Invited Speaker: Kronos, Cyclacel, Ideaya biosciences; Non-Financial Interests, Advisory Role, Clinical trials in minority advisory panel member: Eli Lilly. E. Borazanci: Financial Interests, Personal, Advisory Board: Boehler Life Science Advice, Nanology, TD2, Vivacitas Oncology; Financial Interests, Institutional, Principal Investigator: Biontech, Biosplice, Bristol-Myers Squibb, Corcept, Helix, Merck, Minneamrita Therapeutics. M. Pishvaian: Financial Interests, Personal, Advisory Role: AstraZeneca/MedImmune, Merck, Pfizer, Novartis, TriSalus Life Sciences; Financial Interests, Personal, Royalties: Perthera patient matching algorithm, Use patent for veliparib and FOLFOX; Financial Interests, Personal, Stocks/Shares: Perthera; Financial Interests, Institutional, Funding: Tesaro, Seattle Genetics, Pfizer, Arcus Biosciences, IDEAYA Biosciences, Repare Therapeutics, Merck, Tizona Therapeutics, Inc., Novartis, Takeda, Hutchison MediPharma, BioMed Valley Discoveries, Amgen, Ambrx; Non-Financial Interests, Personal, Other: RenovoRx. A. Turk: Financial Interests, Personal, Advisory Board: Exelixis; Financial Interests, Institutional, Funding: Lilly. R.D. Carvajal: Financial Interests, Personal, Advisory Role: Merck, Aura Biosciences, Castle Biosciences, Immunocore, PureTech, Sorrento Therapeutics, Chimeron Bio, Rgenix, InxMed, Pierre Fabre, TriSalus Life Sciences, Iovance Biotherapeutics, Oncosec, Regeneron, Genzyme; Financial Interests, Institutional, Advisory Role: Amgen, Astellas Pharma, AstraZeneca, Bristol-Myers Squibb/Medarex, Corvus Pharmaceuticals, IDEAYA Biosciences, Mirati Therapeutics, Novartis, Pfizer, Plexxikon, Roche/Genentech; Financial Interests, Personal, Speaker’s Bureau: Bristol-Myers Squibb/Medarex; Financial Interests, Institutional, Funding: Amgen, Astellas Pharma, AstraZeneca, Bayer, Bellicum Pharmaceutics, Bristol-Myers Squibb, Corvus Pharmaceuticals, Lilly, Immunocore, Incyte, Macrogenics, Merck, Mirati Therapeutics, Novartis, Pfizer, Plexxikon, Roche/Genentech, Array BioPharma, IDEAYA Biosciences, Regeneron. C. Mantia: Financial Interests, Institutional, Invited Speaker, Institutional funding for research: Bristol Myers Squibb. G. Giaccone: Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Institutional, Research Grant: Karyopharm. Z. Mounir: Financial Interests, Personal, Full or part-time Employment: IDEAYA Biosciences; Financial Interests, Personal, Stocks/Shares: IDEAYA Biosciences; Financial Interests, Personal, Other, Honoraria: IDEAYA Biosciences; Financial Interests, Personal, Royalties: IDEAYA Biosciences, Novartis; Financial Interests, Personal, Other, Travel, accommodation: IDEAYA Biosciences. A. Patel: Financial Interests, Institutional, Full or part-time Employment: IDEAYA. M. Maurer: Financial Interests, Personal, Full or part-time Employment: IDEAYA Biosciences; Financial Interests, Personal, Stocks/Shares: IDEAYA Biosciences, BMS; Financial Interests, Personal, Other, Travel, accommodation: IDEAYA Biosciences. C. Neilan: Financial Interests, Institutional, Full or part-time Employment: IDEAYA Biosciences; Financial Interests, Institutional, Stocks/Shares: IDEAYA Biosciences. D. Rajendran: Financial Interests, Personal, Full or part-time Employment: IDEAYA Biosciences, UNITY BIOTECHNOLOGY; Financial Interests, Personal, Stocks/Shares: IDEAYA Biosciences. U. Ganesan: Financial Interests, Personal, Full or part-time Employment: IDEAYA Biosciences; Financial Interests, Personal, Stocks/Shares: IDEAYA Biosciences, Syneos Health, Regeneron. J. Hinkle: Financial Interests, Personal, Advisory Role: IDEAYA Biosciences. A.W. Tolcher: Financial Interests, Institutional, Advisory Board, Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is the CEO and Founder.: Adagene, Inc., ARO Biotherapeutics, BIOINVENT, Boehringer Ingelheim International GmbH, Deka Biosciences, Eleven Bio, ELUCIDA, EMD Serono/ MERK KGaA, IMMUNOME, NBE Therapeutics, Pelican, Pieris Pharma, Pyxis Oncology, Vincerx, Zymeworks Inc., MIRATI; Financial Interests, Institutional, Other, Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is the CEO and Founder.: Asana BioSciences, LLC., Axlmmune, Bayer, Gilde Healthcare Partners, HBM Partners, Immunomet Therapeutics, Inc., Karma Oncology, Menarini Ricerche, Mersana, NANOBIOTIX, Partner Therapeutics, Pfizer Inc., PIERRE FABRE, RYVU Therapeutics, Seattle Genetics, SOTIO Biotechnology Co., Spirea Limited Inc., Transcenta Therapeutics Inc., Trillium Therapeutics Inc., AbbVie, Inc, AGENUS, Inc., Ascentage, Mekanistic Therapeutics; Financial Interests, Institutional, Other, Fees for consulting for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is the President and Founder.: Aclaris Therapeutics; Financial Interests, Institutional, Other, Fees for consulting for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is President and Founder.: Daiichi Sankyo, Inc.; Financial Interests, Institutional, Other, NOTE: Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is President and Founder.: Immuneering, Impact Therapeutics US, Inc., Ocellaris Pharma, Inc. & Eli Lilly, SK Life Science, Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd; Financial Interests, Institutional, Advisory Board, NOTE: Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is President and Founder.: ZielBio, Inc., Ikena Oncology, Hiber Cell, Inc.; Financial Interests, Institutional, Invited Speaker, Dr. Tolcher is the Director of Research, CEO and Founder of NEXT Oncology: NEXT Oncology; Financial Interests, Personal, Stocks/Shares: Pyxis Oncology; Financial Interests, Institutional, Invited Speaker, Fees for studies are paid for all study related costs, to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which Dr. Anthony Tolcher is CEO and Founder: Adagene Inc, AbbVie, Inc, Aminex Therapeutics, Inc., Amphivena Therapeutics, Inc., Apros Therapeutics, Inc., Arcellx, Inc., ARMO Biosciences, Arrys Therapeutics, Inc., Artios Pharma Limited, Asana BioSciences, LLC., Ascentage Pharma Group Inc., Astex Pharmaceuticals, Basilea Pharmaceutica International Ltd, BioInvent International AB, BioNTech RNA Pharmaceuticals GmbH, BioNTech RNA Pharmaceuticals GmbH, Birdie Biopharmaceuticals, HK Ltd., BJ Bioscience Inc., Boehringer Ingelheim Pharmaceutical, Inc., Boston Biomedical, Inc., Calgent Biotechnology Co., Ltd., Codiak BioSciences, Inc., CStone Pharmaceuticals (Suzhou) Co., Ltd., Cybrexa Therapeutics, Inc., Daiichi Sankyo Inc., Deciphera Pharmaceuticals, LLC, eFFECTOR Therapeutics, Inc, Eli Lilly and Company, EMD Serono, Gilead Sciences, Inc., GlaxoSmithKline Research & Development Limited, IDEAYA Biosciences, Haihe Biopharma Co., Ltd., Heat Biologics, IDEAYA Biosciences, ImmuneOncia Therapeutics, Inc., IMPACT Therapeutics, Inc., Inhibrx, Inc., Innate Pharma SA, Janssen Research & Development, K-Group Beta, Inc., KeChow Pharma, Inc., Kiromic Biopharma, Inc, Mabspace Biosciences (Suzhou) Co., Limited, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Mersana Therapeutics, Inc., Mirati Therapeutics, Inc., NatureWise Biotech & Medicals Corporation, Navire Pharma Inc., NBE-Therapeutics AG, NextCure, Inc, Nitto BioPharma, Inc., Odonate Therapeutics, Inc., Pelican Therapeutics, Inc., Petra Pharma, Pfizer, Inc., Pieris Pharmaceuticals, Inc., PMV Pharmaceuticals, Inc., Qilu Puget Sound Biotherapeutics Corporation, Samumed, LLC, Seattle Genetics, Inc., Spring Bank Pharmaceuticals, Inc., Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd., Symphogen A/S, Syndax Pharmaceuticals Inc., Synthorx, Inc., Takeda, Tizona Therapeutics, Zymeworks Inc.; Financial Interests, Institutional, Invited Speaker: ADC Therapeutics SA, Agenus Inc.; Financial Interests, Institutional, Invited Speaker, Fees for studies are paid for all study related costs, to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which Dr. Anthony Tolcher is CEO and Founder.: ORIC Pharmaceuticals; Non-Financial Interests, Principal Investigator: AbbVie, Inc; Non-Financial Interests, Principal Investigator, Fees for studies are paid for all study related costs, to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which Dr. Anthony Tolcher is CEO and Founder: ABL Bio Inc., Adagene Inc, ADC Therapeutics SA, Agenus Inc., Aminex Therapeutics, Inc., Amphivena Therapeutics, Inc., Apros Therapeutics, Inc., Arcellx, Inc., ARMO Biosciences, Arrys Therapeutics, Inc., Artios Pharma Limited, Asana BioSciences, LLC., Ascentage Pharma Group Inc., Astex Pharmaceuticals, Basilea Pharmaceutica International Ltd, BioInvent International AB, BioNTech RNA Pharmaceuticals GmbH, Birdie Biopharmaceuticals, HK Ltd., BJ Bioscience Inc., Boehringer Ingelheim Pharmaceutical, Inc., Boston Biomedical, Inc., Calgent Biotechnology Co., Ltd., Codiak BioSciences, Inc., CStone Pharmaceuticals (Suzhou) Co., Ltd., Cybrexa Therapeutics, Inc., Daiichi Sankyo Inc., Deciphera Pharmaceuticals, LLC, eFFECTOR Therapeutics, Inc, Eli Lilly and Company, EMD Serono, Gilead Sciences, Inc., IDEAYA Biosciences, GlaxoSmithKline Research & Development Limited, Haihe Biopharma Co., Ltd., Heat Biologics, ImmuneOncia Therapeutics, Inc., IMPACT Therapeutics, Inc., Inhibrx, Inc., Innate Pharma SA, Janssen Research & Development, K-Group Beta, Inc., KeChow Pharma, Inc.