680P - First results from the phase I trial of the ATR inhibitor, ART0380, in advanced solid tumors

Background

Ataxia telangiectasia and Rad3-related (ATR) is a critical protein in sensing DNA damage and activating the DNA damage checkpoint. ART0380 is a potent and selective, orally administered ATR inhibitor. This is the first report of the ongoing phase I trial (NCT04657068).

Methods

Patients (pts) with advanced solid cancers received escalating doses of ART0380 on a continuous daily (QD) or intermittent (3 days on, 4 days off) schedule. Investigators were guided to enroll pts with cancers that harbored DNA damage response deficiencies as identified by the Artios DcoDeR platform. Key study objectives included evaluation of safety and tolerability, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics.

Results

49 pts were dosed with ART0380 monotherapy: 39 pts on intermittent doses between 100mg and 1200mg, and 10 pts on QD doses of 200mg and 400mg. PK data show ART0380 is rapidly absorbed followed by immediate decline to a low level succeeded by a longer mean elimination half-life of 8.3 hours. ART0380 exposure is dose proportional with increasing dose from 100mg to 1200mg in terms of Cmax and AUC0-24ss. The recommended phase II doses have been established as 600mg intermittent and 200mg QD. Approximately 36% of pts experienced the only Grade 3 treatment-related adverse event of anemia. Pts on QD dosing experienced fewer unplanned dose interruptions due to adverse events compared to intermittent dosing. Confirmed partial responses were observed in 3 pts with endometrial adenocarcinoma and 1 pt with anal cancer. One pt with cholangiocarcinoma had a profound reduction in their tumor marker associated with a reduction in non-measurable disease. There was a 25% confirmed objective response rate in pts with measurable disease treated on the QD regimens. Target engagement was demonstrated via γH2AX modulation in circulating tumor cells. Exploratory biomarker analysis is underway.

Conclusions

These early data demonstrate that ART0380 dosed both continuously and intermittently is well tolerated and clinically active. ART0380 has a PK profile conducive with both intermittent and continuous dosing. The DcoDeR platform enabled the successful identification of pts with cancers sensitive to ATR inhibition.

Clinical trial identification

NCT04657068.

Editorial acknowledgement

Legal entity responsible for the study

Artios Pharma Limited.

Funding

Artios Pharma Limited.

Disclosure

K.N. Moore: Financial Interests, Personal, Advisory Board: Aadi, AstraZeneca, Alkemeres, Blueprint Pharma, Clovis, Caris, Duality, Eisai, GSK, Genentech/Roche, Immunogen, IMab, Merck, Mersana, Mereo, OncXerna, OncoNova, Novartis, Pannavance, VBL Therapeutics, Verastem, Zentalis; Financial Interests, Institutional, Research Funding: PTC Therapeutics, Eli Lilly and Company, Verastem, Merck, GSK, Genentech; Financial Interests, Institutional, Member of Board of Directors: GOG Foundation , ASCO. M.R. Patel: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Janssen, Accutar; Financial Interests, Institutional, Local PI, Institution Received Research Funding: Daiichi Sankyo. G.S. Falchook: Financial Interests, Institutional, Advisory Board, 2018 : FujiFilm; Financial Interests, Institutional, Advisory Board, 7/24/2020, 9/17/2021: Silicon; Financial Interests, Institutional, Advisory Board, 3/10/21: Navire; Financial Interests, Institutional, Advisory Board, 4/22/21: Turning Point; Financial Interests, Institutional, Advisory Board, 10/2/21: Predicine; Financial Interests, Institutional, Advisory Board, 10/26/21: Inspirna; Financial Interests, Institutional, Advisory Board, 10/28/21: Regeneron; Financial Interests, Personal, Advisory Board, 6/2010, 3/2011: EMD Serono; Financial Interests, Institutional, Advisory Board, 1/18/22 and 8/17/22: Jubilant; Financial Interests, Institutional, Advisory Board, 6/4/22: BostonGene; Financial Interests, Institutional, Advisory Board, 9/30/22: AbbVie; Financial Interests, Personal, Invited Speaker, 2019 : Total Health Conferencing; Financial Interests, Personal, Invited Speaker, 2020 : Rocky Mountain Oncology Society; Financial Interests, Personal, Other, Travel, for work and/or research related to institution, 2015: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel, for work and/or research related to institution, 2011, 2012, 2013: EMD Serono; Financial Interests, Personal, Other, Travel, to present research at a conference (Cholangiocarcinoma Foundation meeting), 2018: Fujifilm; Financial Interests, Personal, Other, Travel, to present research at a conference (ESGO), 2013: Millennium; Financial Interests, Personal, Other, Travel, for work and/or research related to institution, at least once yearly: Sarah Cannon Research Institute (employer); Financial Interests, Personal, Other, Travel, to present research at a conference (WCLC), 2022: Amgen; Financial Interests, Personal, Other, Travel, to present research at a conference (ESMO), 2022: Synthorx / Sanofi; Financial Interests, Institutional, Advisory Board, Scientific advisory board 11/18/22: Teon Therapeutics; Financial Interests, Institutional, Advisory Board, 12/8/22: Merck; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Institutional, Local PI: 3-V Biosciences, Abbisko, AbbVie, ABL Bio ADC Therapeutics, Accutar, Aileron, American Society of Clinical Oncology, Amgen, ARMO/Eli Lilly, Artios, AstraZeneca, BeiGene, Bioatla, Bioinvent, Biothera, Bicycle, Boehringer Ingelheim, Celldex, Celgene, Ciclomed, Curegenix, Curis, Cyteir, Daiichi Sankyo, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Epizyme, Erasca, Exelixis, GSK, Freenome, Fujifilm, Genmab, Hutchison MediPharma, IGM Biosciences, Ignyta, ImmunoGen/MarcoGenics, Incyte, Jacobio, Jounce, Kolltan, Loxo/Bayer, MedImmune, Millennium, Merck, miRNA Therapeutics, Molecular Templates, National Institutes of Health, Navire, NiKang, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Precision Oncology, Prelude, PureTech, Pyramid, RasCal, Regeneron, Rgenix, Ribon, Samumed, Sapience, Silicon, Simcha, Strategia, Syndax, Synthorx/Sanofi, Taiho, Takeda, Tarveda, Teneobio, Tesaro, Tocagen, Turning Point, U.T. MD Anderson Cancer Center, Vegenics, Xencor; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial: Black Diamond, Jubilant, Relay, Seagen, Sirnaomics, Metabomed, Agenus, Tallac, Zhuhai Yufan, Mirati, Immunitas, Jazz Pharmaceuticals, Bayer. E. Fontana: Financial Interests, Personal, Invited Speaker: CARIS Life Science, Repair Therapeutics; Financial Interests, Personal, Other, Conference attendance: Sapience Pharma; Financial Interests, Personal, Full or part-time Employment: Hospital Corporation of America (HCA) International; Financial Interests, Personal, Officer: EORTC; Financial Interests, Institutional, Invited Speaker: Repair Therapeutics, Amgen, Taiho Pharmaceutical; Financial Interests, Institutional, Local PI: Bicycle Therapeutics, Artios Pharma, Seagen, Nurix Therapeutics, BioNTech SE, Relay Therapeutics, Pfizer, Roche, Daiichi Sankyo, Gilead Science, Basilea Pharmaceutica, Jiangsu Hengrui Medicine, Mereo Biopharma, HUTCHMED, Merus, Crescendo Biologics, GSK plc, BeiGene, Turning Point Therapeutics, Sapience Pharma; Non-Financial Interests, Advisory Role: Vivan Therapeutics. B. Bashir: Financial Interests, Personal, Advisory Board: Merck/Eisai; Financial Interests, Institutional, Principal Investigator: Amgen, Artios, Bicycle Therapeutics, Boehringer Ingelheim, Girstone Bio, Ikena Oncology, Jazz Pharmaceuticals, KAHR Medical, Lyell immunopharma, Merck, Pionyr Immunopharma, RASCAL Therapeutics, Syros Pharmaceuticals, Tarveda Therapeutics. C.A. Perez: Financial Interests, Institutional, Local PI: Accutar Biotech, Kinnate Biopharma, Relay Therapeutics, Seagen Inc., Kura Oncology, Hyamab Inc., Xilio Therapeutics, Elucida Oncology, Tallac Therapeutics, Ribbon Therapeutics, Mirati Therpeutics, Elpiscience Biopharmaceuticals, Dracen Pharmaceuticals, Zhuhai Yufan Biotechnologies Co., Genentech, Inc., Jazz Pharmaceuticals, Artios Pharma. M. Barve: Financial Interests, Personal, Full or part-time Employment, Private practice: Texas Oncology/ US Oncology; Financial Interests, Personal, Stocks/Shares, Physician shareholder: Texas Oncology; Financial Interests, Institutional, Local PI, Research funding to the institution: 1200 Pharma, Agenus, Amgen, Inc., Artios Pharma Limited, Astellas Pharma Global Development, Inc., AstraZeneca, Bayer Healthcare Pharmaceuticals, Inc., BeiGene USA, Inc., Bicycle Therapeutics, Bio-Path Holdings, Black Diamond Therapeutics, Boehringer Ingelheim, BriaCell Therapeutics, Bristol Myers Squibb, Compass Therapeutics Inc., Coordination Pharma, Corvus Pharmaceuticals, CStone Pharmaceuticals, Dialectic Therapeutics, Inc., Elevation Oncology, Eli Lilly and Company, EMD Serono, EpicentRx Inc., Erasca, Eutilex, Exelixis Inc., F. Hoffmann-La Roche Ltd. (Genentech), Gan & Lee Pharmaceuticals, Genprex Inc., Gilead Sciences, GSK, Gradalis, Harpoon Therapeutics, Inc., IGM Biosciences, Inc., ImmuneOnco Biopharmaceutics (Shanghai), Immvira Pharma Co. Ltd., Incyte Corporation, Jiangsu Alphamab Biopharmaceuticals Co., Ltd., Jiangsu HengRui Medicine, Klus Pharma, Inc., Kronos Bio, LaNova Medicines Ltd., Loxo Oncology, MedImmune, Merck Sharp & Dohme Corp., Mersana Therapeutics, Inc., Mirati Therapeutics, Inc., Molecular Templates Inc., Monte Rosa Therapeutics, Nektar Therapeutics, NeoImmuneTech, Inc., Nitto BioPharma, Inc., Novartis Pharmaceuticals, Pfizer, Pionyr Immunotherapeutics, Protagonist Therapeutics, Inc., Qilu Puget Sound Biotherapeutics Corporation, Qurient Co., Ltd., RAPT Therapeutics, Inc., Revolution Medicines, Sanofi, Scholar Rock, Sermonix Pharmaceuticals, Servier Pharmaceuticals, Stemline Therapeutics, Inc., Sumitomo Dainippon Pharma Oncology (SDPO), Suzhou Kintor Pharmaceuticals, Suzhou Transcenta Therapeutics Co., Ltd., SynerGene Therapeutics, Synthorx, Tesaro, Inc., Theratechnologies Inc., Verastem, Inc., Xbiotech. S. Ulahannan: Financial Interests, Personal, Advisory Board: Array, Incyte, Bayer, Syros, Eisai, AstraZeneca; Financial Interests, Institutional, Local PI: AstraZeneca, AbbVie, Adlai Nortye, Arqule, Atreca, BI, BMS, Celgene, Ciclomed LLC, Erasca, Evelo Biosciences, Exelexis, G1 Therapeutics, GSK, IGM biosciences, Incyte, isofol, Klus pharma, Macrogenics, merck, Mersana, Oncomed, Pfizer, Regeneron, Revolution Medicines, Synermore Biologics, Takeda, Tarveda Therapeutics, Tesaro, Tempest, Vigeo, Tvardi, hutch med. H. Milward, S. Menon: Financial Interests, Personal, Full or part-time Employment: Artios Pharma Ltd.; Financial Interests, Personal, Stocks/Shares: AstraZeneca. A. Fielding, B. Harrop, S. Busacca, S. Holt, I. Smith: Financial Interests, Personal, Full or part-time Employment: Artios Pharma Ltd. N. Little, T. Coleman: Financial Interests, Personal, Financially compensated role: Artios Pharma Ltd. A. Wilby: Financial Interests, Personal, Full or part-time Employment: Seda Pharmaceutical Development Services. D. Headley: Financial Interests, Personal, Full or part-time Employment: Artios Pharma Ltd; Financial Interests, Personal, Stocks/Shares: Amgen, AbbVie, Eli Lilly and Company. M.L. Johnson: Financial Interests, Institutional, Other, Consulting: AbbVie, Amgen, Arcus Biosciences, Arrivent, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Calithera Biosciences, Daiichi Sankyo, EcoR1, Genentech/Roche, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, Ideaya Biosciences, Immunocore, iTeos, Janssen, Jazz Pharmaceuticals, Merck, Mirati Therapeutics, Molecular Axiom, Novartis, Oncorus, Pyramid Biosciences, Regeneron Pharmaceuticals, Revolution Medicines, Sanofi-Aventis, Seagen, Synthekine, Takeda Pharmaceuticals, Turning Point Therapeutics, VBL Therapeutics; Financial Interests, Institutional, Research Grant: AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, Black Diamond, BeiGene, BerGenBio, BioAtla, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Carisma Therapeutics, Checkpoint Therapeutics, City of Hope National Medical Center, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchinson MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunitas Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Kartos Therapeutics, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Sanofi, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL Therapeutics, Y-mAbs Therapeutics.