450O - Initial monotherapy results of a phase I first-in-human study of ULK1/2 inhibitor DCC-3116 alone and in combination with MAPK pathway inhibition

Background

Mitogen-activated protein kinase (MAPK) pathway inhibition activates Unc-51–like autophagy activated kinase (ULK) 1/2 and initiates autophagy to promote survival of RAS/RAF mutant cancers. DCC-3116, a first-in-class potent and selective ULK inhibitor, demonstrated preclinical antitumour activity in combination with MAPK pathway inhibitors. Here, we describe initial DCC-3116 monotherapy results from an ongoing phase I study.

Methods

This phase I, multicentre, open-label, first-in-human study evaluates DCC-3116 alone and in combination with MAPK pathway inhibition in patients (pts) with MAPK pathway mutant locally advanced or metastatic solid cancers. Oral DCC-3116 is administered twice daily (BID) in 28-day cycles (3+3 escalation). Primary objective is safety; additional objectives include antitumour activity, pharmacokinetics (PK in plasma), and pharmacodynamics (PD; phosphorylation of ULK substrate ATG14 in peripheral blood mononuclear cells [PBMCs]).

Results

As of March 11, 2022, 11 pts were enrolled at doses ranging from 50–200 mg BID; no dose-limiting toxicities (DLTs) were observed. Drug-related treatment-emergent adverse events (TEAEs) were ≤Grade (G) 2 and all occurred in only 1 pt each, except fatigue in 5 pts; none were serious or resulted in dose reduction. Most common (≥20%) TEAEs regardless of relatedness were fatigue, anaemia, and vomiting. Nine G ≥3 TEAEs occurred; only 1 occurred in >1 pt (G3 anaemia, 3 pts). At Day 15, DCC-3116 100 mg BID produced ∼70% (total) and ∼40% (estimated unbound) of target exposure required for ULK inhibition based on mouse PK/PD studies (Table). At this dose, phospho-ATG14 in PBMCs decreased by ∼60% compared to baseline. An update will be reported at the meeting. Table: 450O

Day 15 PK

^aPK: n = 3; 1 patient discontinued before Day 15. b Imputed predose concentration to 12h time point. c In vitro PPB Fu 0.213. d Mouse AUC0–12h = 11123 h*ng/mL; unbound = 4049 h*ng/mL (in vitro PPB Fu 0.364). AUC, area under the curve; BID, twice daily; Cmax, maximum concentration; CV, variability; Fu, unbound fraction; P, pending analysis; PK, pharmacokinetics; PPB, plasma protein binding.

Conclusions

At data cutoff, DCC-3116 monotherapy had an acceptable safety profile with no DLTs at doses that achieved a PD effect, supporting continued dose escalation and planned combination with MAPK pathway inhibition.

Clinical trial identification

NCT04892017.

Editorial acknowledgement

Medical writing and editorial support was provided by Lauren Hanlon, PhD, of AlphaBioCom, LLC (King of Prussia, PA, USA) and was funded by Deciphera Pharmaceuticals, LLC (Waltham, MA, USA).

Legal entity responsible for the study

Deciphera Pharmaceuticals, LLC.

Funding

Deciphera Pharmaceuticals, LLC.

Disclosure

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, Haihe Biopharma Co., Ltd., Heat Biologics, IDEAYA Biosciences, 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., GlaxoSmithKline Research & Development Limited, 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. D.S. Hong: Financial Interests, Personal, Other, All companies listed are classified as Consulting, Speaker or Advisory role: Adaptimmune, Alpha Insights, Acuta, Alkermes, Amgen, Aumbiosciences, Axiom, Baxter, Bayer, Boxer Capital, BridgeBio, COR2ed, COG, Cowen, Ecor1, Gennao Bio, Genentech, Gilead, GLG, Group H, Guidepoint, HCW Precision, ImmunoGen, Infinity, Janssen, Liberium,; Financial Interests, Personal, Other, All are Advisory and or Advisory/Founder: Molecular Match (Advisor), OncoResponse (Founder, Advisor), Telperian (Founder,Advisor); Financial Interests, Institutional, Research Grant: AbbVie, Adaptimmune, Adlai-Nortye, Amgen, Astra-Zeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Deciphera, Eisai, Endeavor, Erasca, F. Hoffmann-La Roche, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa Kirin, Lilly, LOXO, Merck, M. A. Vandross: Financial Interests, Institutional, Full or part-time Employment, Phase I investigator: NEXT Oncology; Financial Interests, Institutional, Invited Speaker, Phase I study: Mabwell, AbbVie, AstraZeneca, Ascentage Pharma, Asana Bio, BioOneCure, BJ Bioscience, Cybrexa Therapeutics, Deciphera, Elpiscience Biopharma, Nanjing Immunophage Biotech, Chugai Pharmaceutical, Lyvgen Biopharma, NGM Bio, OncoResponse, Zhuhai Yufan Biotecnologies, Immunomedics, Inc, siRNAomics, Sorrento therapeutics, Vincerx, Exelixis, Xilio Development Inc, Ziel Bio; Financial Interests, Institutional, Invited Speaker, Phase I: Nitto therapeutics. R. Amaravadi: Financial Interests, Personal, Advisory Board: Deciphera, Pinpont Therapeutics; Financial Interests, Personal, Ownership Interest: Pinpoint Therapeutics; Financial Interests, Institutional, Invited Speaker: Deciphera, Bristol Myers Squibb, Novartis; Financial Interests, Institutional, Research Grant: Pinpoint Therapeutics. C. Psoinos: Financial Interests, Personal, Full or part-time Employment: Deciphera Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: Deciphera Pharmaceuticals, Johnson & Johnson, Pfizer, AbbVie, Viatris. D. Brennan: Financial Interests, Personal, Full or part-time Employment: Deciphera Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: Deciphera Pharmaceuticals. M.L. Sherman: Financial Interests, Personal, Full or part-time Employment: Deciphera Pharmaceuticals; Financial Interests, Personal, Invited Speaker: Pieris Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: Deciphera Pharmaceuticals, Pieris Pharmaceuticals. R. Ruiz-Soto: Financial Interests, Personal, Full or part-time Employment: Deciphera Pharmaceuticals, LLC; Financial Interests, Personal, Stocks/Shares: Deciphera Pharmaceuticals, LLC, ImmunoGen; Financial Interests, Personal, Other, I am an inventor in 3 patents with ImmunoGen, I transferred the rights to ImmunoGen. I have not received (and I will not receive) any royalties: ImmunoGen; Financial Interests, Personal, Other, I am an inventor in pending patents at Deciphera. I have transferred the rights to Deciphera, I have not received (and will not receive) any royalties: Deciphera. L. Viswanathan: Financial Interests, Institutional, Full or part-time Employment, Employee of the company: Deciphera Pharmaceuticals; Financial Interests, Personal, Stocks/Shares, Own RSUs and ESPPs: Deciphera Pharmaceuticals; Other, Previously employed at Vertex Pharmaceuticals (September 2010-March 2021): Vertex Pharmaceuticals. K. Sprott: Financial Interests, Institutional, Full or part-time Employment: Deciphera Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: Deciphera Pharmaceuticals, Stablix. F.J. Reu: Financial Interests, Personal, Full or part-time Employment, VP Early Clinical Development: Deciphera Pharmaceuticals, LLC; Financial Interests, Personal, Stocks/Shares: Deciphera Pharmaceuticals, LLC, Bristol-Myers Squibb. C.D. Weekes: Financial Interests, Personal, Other, Honoraria: Celgene, Merrimack, Lilly, Bayer; Financial Interests, Personal, Advisory Role: Celgene, Merrimack, Ipsen; Financial Interests, Personal and Institutional, Funding: Millennium, Celgene, Bayer, Genentech/Roche, AbbVie, Lilly, AstraZeneca, Gilead Sciences, Ipsen, Halozyme; Financial Interests, Personal, Other, Travel, Accomodations, Expenses: Lilly, Celgene, Bayer.