Background

CIRT is a potent, selective pan CLK/DYRK inhibitor that modulates alternative splicing. CIRT is being evaluated in two ongoing phase I studies, a first in human (FIH) and combination trial. Preliminary data from these studies are presented.

Methods

The FIH study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of CIRT in pts with advanced solid tumors. The FIH trial included dose escalation (10-60mg daily (qd), 80 mg 2 days on/5 days off (2/5), and 80 mg 7 days on/7 days off (7/7)) and dose finding (30mg qd and 40-160mg 5 days on/2 days off (5/2)) cohorts. The phase Ib study combines CIRT with abiraterone acetate, FOLFIRI-panitumumab, or docetaxel in advanced/metastatic CRPC, CRC, and NSCLC, respectively.

Results

Sixty-five subjects participated in the FIH trial. Systemic exposures of CIRT were dose-dependent with an effective terminal half-life > 24 hours. Drug accumulation was 1-2 fold using the 5/2 schedule. PK/PD evaluation from whole blood provided evidence of modulation of CLK1 and SRSF5 with the latter showing a greater effect with increasing exposure. The MTD of CIRT was 120mg (5/2 schedule). Safety and DLTs were as follows: the most common adverse events (AEs) were diarrhea (60%), nausea (60%), fatigue (40%), and vomiting (38.4%); Grade 3 or higher AEs included anemia (15.4%) and diarrhea (10.8%); DLTs included elevated LFTs (40mg qd, 1 subject), diarrhea (80mg 7/7 and 120mg 5/2, 2 subjects), and rash (160 mg 5/2, 1 subject). CIRT monotherapy led to tumor shrinkage (> 10% to < 29%) in 5 pts, PSA30 in 3 CRPC pts, and long-term stable disease (on study > 6 cycles) in 10 pts. In addition, 4 pts with CRPC (1 ARV7+) had a decline in circulating tumor cells. In the phase Ib combination study, in CRPC subjects that would be considered hormonal therapy resistant, we observed 2 PSA50s and 2 PSA30s among 5 subjects treated with at least 2 cycles of therapy.

Conclusions

Findings from these 2 studies provide evidence of clinical activity with manageable toxicity for CIRT in an advanced cancer patient population and suggest hormonal therapy resistance can be overcome in CRPC subjects when CIRT is combined with abiraterone acetate.

Clinical trial identification

NCT03355066, November 28, 2017 NCT05084859: October 20, 2021.

Legal entity responsible for the study

Biosplice Therapeutics.

Funding

Biosplice Therapeutics.

Disclosure

A. Scott: Financial Interests, Personal, Stocks/Shares: Johnson & Johnson/Janssen; Financial Interests, Personal, Advisory Role: Exelixis, QED, Pfizer; Financial Interests, Personal, Sponsor/Funding, Research Funding: Exelixis, Genetech, Incyte, FivePrime, Merck; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Exelixis, QED. E. Borazanci: Financial Interests, Personal, Advisory Role: Imaging endpoints, BioNTech AG, Vivacitas Oncology, NanOlogy, Boehler Life Sciene Advice, TD2; Financial Interests, Personal, Invited Speaker: Ipsen; Financial Interests, Institutional, Research Grant, Research Funding: Bristol-Myers Squibb, Pharmacyclics, Idera, Daiichi Sankyo, Minneamrita Therapeutics, Merck, Helix, BioNTech AG, Corcept Therapeutics; Financial Interests, Institutional, Principal Investigator, Research Funding: Biosplice Therapeutics. G.S. Falchook: Financial Interests, Institutional, Advisory Board: FujiFilm, Silicon, Navire, Turning Point, Predicine, Inspirna, Regeneron; Financial Interests, Personal, Advisory Board: EMD Serono; Financial Interests, Personal, Invited Speaker: Total Health Conferencing, 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, for work and/or research related to institution, 2018: Fujifilm; Financial Interests, Personal, Other, Travel, for work and/or research related to institution, 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, Royalties: Wolters Kluwer; Financial Interests, Institutional, Invited Speaker: 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, Black Diamond, Boehringer Ingelheim, Celldex, Celgene, Ciclomed, Curegenix, Curis, Cyteir, Daiichi, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Epizyme, Erasca, Exelixis, Freenome, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, IGM Biosciences, Ignyta, ImmunoGen/MarcoGenics, Incyte, Jacobio, Jounce, Jubilant, Kolltan, Loxo/Bayer, MedImmune, Millennium, Merck, miRNA Therapeutics, Molecular Templates, National Institutes of Health, Navire, NiKang, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Pyramid, Precision Oncology, Prelude, PureTech, RasCal, Regeneron, Relay, Rgenix, Ribon, Samumed, Sapience, Seagen, Silicon, Simcha, Sirnaomics, Strategia, Syndax, Synthorx/Sanofi, Taiho, Takeda, Tarveda, Teneobio, Tesaro, Tocagen, Turning Point, U.T. MD Anderson Cancer Center, Vegenics, Xencor. R. Bordoni: Financial Interests, Personal, Advisory Role: AstraZeneca, Guardant Health, PhillipsGilmore Oncology; Financial Interests, Personal, Invited Speaker: AstraZeneca, Guardant Health, OncLive Clinical Congress Consultants, NeoGenomics. A. Starodub: Financial Interests, Personal, Invited Speaker: BMS. N.J. Lakhani: Financial Interests, Personal, Advisory Board: Innovent Biologics; Financial Interests, Personal, Advisory Board, Participation in Ad Board: Ikena, SK Life Sciences; Financial Interests, Institutional, Invited Speaker: ALX Therapeutics, Ascentage, Constellation Pharma, Alpine Biosciences, Forty Seven, Merck, Pfizer, Regeneron, Symphogen, InhibRx, Seagen, Sapience Therapeutics, Jounce, Northern Biologics, Odonate, Loxo/Lilly, Ikena, Mersana Therapeutics, Astellas, Celgene, Helsinn, Shattuck Labs, Samumed, Glaxo Smith Kline, Alkermes, Servier, Samumed, Tizona Therapeutics, Gilead. E. Lam: Financial Interests, Personal, Other, Consultant: Calithera Biosciencees; Financial Interests, Institutional, Invited Speaker, Clinical Trial Funding: Arrowhead Pharmaceuticals, Bristol-Myers-Squibb, Calithera Biosciences, Pfizer, F. Hoffmann-La Roche Ltd., Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Astellas, Forma Therapeutics, Biosplice Therapeutics, Phosplatin Therapeutics, Peloton Therapeutics; Financial Interests, Institutional, Research Grant, Funding for Investigator Initiated Study/Clinical Trial: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. J.S. Wang: Financial Interests, Personal, Invited Speaker, Member of Speaker's Bureau for Tagrisso and Imfinzi: AstraZeneca; Financial Interests, Personal, Invited Speaker, Member of Speaker's Bureau for Lenvima: Eisai; Financial Interests, Personal, Advisory Board, Single Event - Advisory Board Participation: BioNTech, Janssen R&D, Stemline/Menarini; Financial Interests, Institutional, Invited Speaker: 7,8 Pharma, Black Diamond Therapeutics, Klus Pharma, Relay Therapeutics, H3 Biomedicine, Genentech/Roche, ORIC, Celgene/BMS, Olema Therapeutics, Novartis, Portola, MabSpace, Prelude Therapeutics, Treadwell Therapeutics, IGM Biosciences, Forty Seven, StingThera, PureTech Health, Aevi Genomics, Erasca, Artios Pharma, Nurix, Teneobio, BioTheryX, Boehringer Ingelheim, Biosplice, Zymeworks, Bayer Healthcare, ImmunoOnc, Cullinan, Immuno-Gen, Accutar, Blueprint, Hutchinson MediPharma, BioNTech, Macrogenics, TopAlliance, AstraZeneca, Revolution Medicines, Kymab, Clovis Pharma, Qilu Pugent Sound, Ribon Therapeutics, Xencor, LSK BioPartners, Syndax, Sanofi, Daiichi Sankyo, Phoenix Molecular Designs, Cyteir, Bicycle Therapeutics. G. Shapiro: Financial Interests, Personal, Advisory Board: Pfizer, Eli Lilly, G1 Therapeutics, Roche, Merck KGaA/EMD-Serono, Sierra Oncology, Bicycle Therapeutics, Fusion Pharmaceuticals, Cybrexa Therapeutics, Astex, Almac, Ipsen, Bayer, Angiex, Daiichi Sankyo, Seattle Genetics, Boehringer Ingelheim, ImmunoMet, Asana, Artios, Atrin, Concarlo Holdings, Syros, Zentalis, CytomX Therapeutics, Blueprint Medicines; Financial Interests, Institutional, Invited Speaker: Exelixis, Cyteir, Clovis, Samumed, AbbVie, Incyte, AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, CanBas, Cyclacel, Aileron, PUMA; Financial Interests, Personal and Institutional, Invited Speaker: Pfizer, Esperas, Bayer, Lilly, Boehringer Ingelheim, Seattle Genetics, Syros; Other, Patent: Dosage regimen for sapacitabine and seliciclib, issued to Geoffrey Shapiro and Cyclacel Pharmaceuticals: Cyclacel; Other, Pending patent: Compositions and Methods for Predicting Response and Resistance to CDK4/6 Inhibition, with Liam Cornell, PhD (Dana-Farber Cancer Institute): Dana-Farber Cancer Institute. J.C. Sachdev: Financial Interests, Personal, Stocks/Shares: Biosplice Therapeutics; Financial Interests, Personal, Full or part-time Employment: Biosplice Therapeutics; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Immunomedics; Financial Interests, Institutional, Funding, Research: Merck Serono, Pfizer, Tesaro/GSK, Plexxikon, Corcept Therapeutics, AbbVie; Financial Interests, Institutional, Funding, Research Funding: Bolt Biotherapeutics, ImmuneSensor Therapeutics, Syros Pharmaceuticals, Sermonix Pharmaceuticals, Agenus. D. Beaupre: Financial Interests, Personal, Full or part-time Employment, Employee: Biosplice; Financial Interests, Personal, Stocks/Shares, Stock: Biosplice. 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, Apros Therapeutics, Inc., AbbVie, Inc, Aminex Therapeutics, Inc., Amphivena 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., Codiak BioSciences, Inc., Boehringer Ingelheim Pharmaceutical, Inc., Boston Biomedical, Inc., Calgent Biotechnology Co., Ltd., 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., 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. All other authors have declared no conflicts of interest.

Background

BI 907828, a highly potent mouse double minute-2 (MDM2)–p53 antagonist, has demonstrated preclinical antitumour activity, particularly in TP53 wild-type (wt), MDM2-amplified dedifferentiated liposarcoma (DDLPS) models. This phase I study is evaluating BI 907828 in pts with advanced solid tumours. During dose-escalation (phase Ia), the selected recommended dose for expansion (RDE) was 45 mg q3w (Gounder M, 2021).

Methods

During dose-expansion (phase Ib), pts were enrolled to Cohort 1 (TP53wt, MDM2-amplified sarcoma) or Cohort 2 (other TP53wt, MDM2-amplified solid tumours). Pts in Cohort 1 received BI 907828 45 mg q3w; pts in Cohort 2 received 30 or 40 mg on Days 1 and 3 of a 28-day cycle, with a safety run-in of the initial 6 pts per dose level, or 45 mg q3w (biliary tract cancer pts only). The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response and the number of pts with grade ≥3 treatment-related adverse events (AEs).

Results

As of March 2022, 94 pts were enrolled; 50 (53.2%) were male, 57/36 (60.6%/38.3%) had ECOG PS 0/1, respectively; the median number of prior systemic therapies was 2 (range: 0–11). At data cut off, 45/48 pts with advanced LPS were evaluable for tumour response. Disease control rate (complete + partial response (PR) + stable disease) was 93%/88% in pts with DDLPS/well-differentiated LPS (WDLPS), respectively. A confirmed PR was achieved in 5 pts (2 DDLPS, 3 WDLPS); 3 pts (2 DDLPS, 1 WDLPS) had an unconfirmed PR. Of the pts enrolled into phase Ia, 5/11 with DDLPS and 4/8 with WDLPS achieved a PFS >10.5 months. For pts with other solid tumours, 2/4 with MDM2-amplified biliary tract cancer and 1 with MDM2-amplified pancreatic adenocarcinoma had a confirmed PR. Of the 46 pts who received the RDE, 22 (47.8%) had grade ≥3 AEs; the most common were neutropenia (21.8%) and thrombocytopenia (19.6%). Serious AEs were experienced by 9 pts; the most common were nausea (n=3), pyrexia, abdominal pain, and thrombocytopenia (n=2 each).

Conclusions

BI 907828 demonstrated antitumour activity and a manageable safety profile in pts with advanced solid tumours, including LPS. The dose-expansion phase is ongoing.

Clinical trial identification

NCT03449381.

Editorial acknowledgement

Medical writing support for the development of this abstract, under the direction of the authors, was provided by Joanna Badawy, BSc, of Ashfield MedComms, an Ashfield Health company, and funded by Boehringer Ingelheim.

Legal entity responsible for the study

Boehringer Ingelheim.

Funding

Boehringer Ingelheim.

Disclosure

P. Schoeffski: Financial Interests, Institutional, Research Grant: CoBioRes NV, Eisai, G1 Therapeutics, PharamaMar, Genmab, Merck, Sartar Therapeutics, ONA Therapeutics; Financial Interests, Personal, Advisory Role: Deciphera, Ellipses Pharma, Blueprint Medicines, Transgene, Exelixis, Boehringer Ingelheim, Studiecentrum voor Kernenergie, SQZ Biotechnology, CRT Pioneer Fund LP, Acendar, PharmaMar, Merck Healthcare KGaA, Ysios Capital . N. Yamamoto: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Eli Lilly, ONO, Chugai, Sysmex, Daiichi-Sankyo, Eisai; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Takeda, ONO, Janssen Pharma, MSD, MERCK, GSK, Sumitomo Dainippon, Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shionogi; Financial Interests, Personal, Advisory Role: Eisai, Takeda, Otsuka, Boehringer Ingelheim, Cimic, Chugai. T. Bauer: Financial Interests, Personal, Speaker’s Bureau: Bayer, Bristol-Myers Squibb, Lilly; Financial Interests, Personal, Advisory Board: Lilly, Pfizer; Financial Interests, Personal, Full or part-time Employment: Tennessee Oncology; Financial Interests, Institutional, Research Grant: Daiichi Sanyko, Incyte, Mirati Therapeutics, MedImmune, AbbVie, AstraZeneca, MabVax, Merck, Lilly, GlaxoSmithKline, Novartis, Pfizer, Genentech/Roche, ImmunoGen, Immuocore, Roche, Bristol-Myers Squibb, Amegen, Moderna Therapeutics, Sanofi, Boehringer Ingelheim, Astellas Pharma, Top Alliance BioScience, Loxo, Janssen, Takeda, Onyx, Foundation Medicine; Financial Interests, Personal, Advisory Role: Loxo, Pfizer, Bayer, AstraZeneca; Financial Interests, Institutional, Other, Travel, accommodation and expenses: Astellas Pharma, AstraZeneca, Celgene, Clovis Oncology, EMD Serono, Genentech, Lilly, Merck, Novartis, Pfizer. M. Patel: Financial Interests, Personal, Speaker’s Bureau: Exelis, Genentech/Roche, Taiho Pharmaceutical, Celgene; Financial Interests, Personal, Advisory Board: Mirati, Daiichi; Non-Financial Interests, Institutional, Funding: Acerta Pharma, ADC Therpeutics, Agenus, Aileron Therapeutics, AZ, Bicycle Therapeutics, BioNTech AG, Boehringer Ingelheim, Calithera Biosciences, Celgene, Checkpoint Therapeutics, CicloMed, Clovs Oncology, Curis, Cyteir, Daiichi Sankyo, eFFECTOR Therapeutics, Lilly, EMD Serono, Evelo Therapeutics, FORMA Therapeutics, Genentech/Roche, Gilead, GSK, H3 Biomedecine, Hengrui Therapeutics, Hutchinson MediPharma, Ignyta, Jacobio, Janssen, Jounce Therapeutics, Klus Pharma, Kymab, Loxo, LSK BioPharma, Lycera, Merck, Millenium, Mirato Therapeutics, Moderna Therapeutics, Pfizer, Phoenix Molecular Designs, Placon, Portola Pharmaceuticals, Prelude Therapeutics, QiLu Pharmaceuticals, PubGene, Revolution Medicines, Ribon Therapeutics, Seven and Eight Biopharmaceuticals, Syndax, Synthorx, Stemline Therapeutics, Taiho Pharmaceutical, Takeda, TopAlliance Biosciences Inc, Vedanta Biosciences, Verastem, Vigeo Therapeutics, xencor, ORIC pharmaceuticals, Artios, Treadwell Therapeutics, MadSpace Biosciences, IgM Biosciences, Puretech, Erasca Inc; Financial Interests, Personal, Advisory Role: Pharmacyclics, Janssen, Pfizer, EMD Serono; Financial Interests, Personal, Other, Travel, accommodation, expenses; Honoraria: Pfizer, Pharmacyclics, Bayer, Janssen Oncology, Genentech. M.M. Gounder: Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Royalties, Patents with MSKCC (GODDESS PRO) (consultant): MSKCC; Financial Interests, Personal, Other, (honorarium; speaker): Medscape, More Health, Physicians Education Resource, touchIME; Financial Interests, Personal, Other, (honorarium; consultant): Athenex, Ayala, Bayer, Boehringer Ingelheim, Daiichi, Epizyme, Karyopharm, Rain, Springworks, Tracon, TYME; Financial Interests, Personal, Other, (consulting fee; consultant): Guidepoint, GLG, Third Bridge, Flatiron Health. J. Geng: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. R. Sailer: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. G. Jayadeva: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. P. Lorusso: Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Personal, Sponsor/Funding: Five Prime Therapeutics; Financial Interests, Personal, Other, Travel, accommodation, expenses: Genentech; Financial Interests, Personal, Advisory Role: Genentech, CytomX Therapeutics, Roche/Genentech, Halozyme, Five Prime Therapeutics, Agenus, Agios, Cybrexa Therapeutics, Sotio, AbbVie, Genmab, Takeda, Tyme, IQvia, Trial to Reduce IDDUM in the Genetically at Risk (TRIGR), Pfizer, ImmunoMet, Black Diamond Therapeutics, GlaxoSmithKline, QED Therpeutics, AstraZenenca, EMD Seronon, Shattuck Labs, Astellas Pharma, Salarius Pharmaceuticals, Silverback Therapeutics, Macrogenics, Kyowa Kirin International, Kineta, Zentalis, Molecular Templates, ABL Boi, SK Life Sciences, ST Cuber, Bayer, I-Mab .

Background

B7-H3 overexpression correlates with poor prognosis in many cancers. DS-7300 is a B7-H3–directed ADC with a topoisomerase I inhibitor payload (DXd). The DS-7300 dose finding study (NCT04145622) showed that DS-7300 was generally well tolerated with early signs of antitumor activity. We present extended follow-up data for a larger cohort of participants (pt) with selected tumor types.

Methods

This Ph 1/2 first-in-human study of DS-7300 enrolled pts with tumors unselected for B7-H3 expression; 12.0 mg/kg was selected for the ongoing expansion Ph. Efficacy/safety analyses included pts in the 4.8- to 16.0-mg/kg cohorts; efficacy was evaluated in pts with ≥2 postbaseline scans or discontinuation for any reason.

Results

As of Jan 21, 2022, 127 pts (median age of 67 years; n=110 male) received DS-7300 (72 in dose escalation; 55 in dose expansion). Pts had a median 5 prior lines of therapy (range, 1-14). Treatment duration range was 0.1-54 weeks with 51 pts (40%) on treatment. Responses were observed in 30/91 evaluable pts (33%) in total (eg, 7/9 pts with SCLC, 2/5 with sqNSCLC, and 16/42 with mCRPC; Table). Among 6 pts with SCLC and a confirmed PR, median duration of response was 4.4 months (95% CI, 2.8-not reached). The overall safety profile is consistent with previously reported results; treatment-emergent adverse events (TEAEs) occurred in 124 pts (98%); the most common (>30%) were nausea (61%), infusion-related reaction (35%), and vomiting (31%). However, higher rates of serious and grade ≥3 TEAEs within a shorter median treatment duration were noted in the 16.0-mg/kg cohort than the 8.0- and 12.0-mg/kg cohorts. Table: 453O

Conclusions

DS-7300 continues to demonstrate evidence of durable antitumor activity in heavily pretreated pts with SCLC, sqNSCLC, and mCRPC. These data support further clinical development of DS-7300, including a Ph 2 dose-optimization study in SCLC (NCT05280470) with starting dose levels of 8 mg/kg and 12.0 mg/kg.

Clinical trial identification

NCT04145622.

Editorial acknowledgement

Medical writing support was provided by Meredith Rogers, MS, CMPP (The Lockwood Group, Stamford, CT, USA) Editorial support was provided in accordance with Good Publication Practice guidelines (ismpp.org/gpp3).

Legal entity responsible for the study

Daiichi Sankyo, Inc.

Funding

Daiichi Sankyo, Inc.

Disclosure

T. Doi: Financial Interests, Institutional, Research Grant, Funding/Principal Investigator: Lilly, MSD, Daiichi Sankyo, Taiho, Novartis, Merck Biopharma, Janssen Pharmaceutical, Boehringer Ingelheim, Pfizer, BMS, AbbVie, Eisai, Chugai Pharma; Financial Interests, Personal, Advisory Role, Consultancy: Janssen Pharmaceutical, Boehringer Ingelheim, Chugai Pharmaceutical, Rakuten Medical , KANEN Pharmaceutical, NanoCarrier , KYOWA KIRIN, Takeda Pharmaceutical , Otsuka Pharmaceutical, SHIONOGI, Sumitomo Pharma, PRA Health Science; Financial Interests, Personal, Invited Speaker: BMS, Ono Pharmaceutical, AstraZeneca, Daiichi Sankyo. M. Patel: Financial Interests, Personal, Speaker’s Bureau: Exelis, Genentech/Roche, Taiho Pharmaceutical, Celgene; Financial Interests, Personal, Advisory Board: Mirati, Daiichi Sankyo; Financial Interests, Personal, Advisory Role: Pharmacyclics/Janssen, Pfizer/EMD Serono; Financial Interests, Personal, Other, Travel, accommodation, expenses: Pfizer, Pharmacyclics, Bayer; Non-Financial Interests, Institutional, Funding: Acerta Pharma, ADC Therapeutics, Agenus, Aileron Therapeutics, AstraZeneca, Bicycle Therapeutics, BioNTech AG, Blueprint, Boehringer Ingelheim, Calithera Biosciences, Celgene, Checkpoint Therapeutics, CicloMed, Clovs Oncology, Curis, Cyteir, Daiichi Sankyo, eFFECTOR Therapeutics, Lilly, EMD Serono, Evelo Therapeutics, FORMA Therapeutics, Genentech/Roche, Gilead, GSK, H3 Biomedicine, Hengrui Therapeutics, Hutchinson MediPharma, Ignyta, Jacobio, Janssen, Jounce Therapeutics, Klus Pharma, Kymab, Loxo, LSK BioPharma, Lycera, Merck, Millenium, Mirato Therapeutics, Pfizer, Phoenix Molecular Designs, Placon, Portola Pharmaceuticals, Prelude Therapeutics, QiLu Pharmaceuticals, PubGene, Revolution Medicines, Ribon Therapeutics, Seven and Eight Biopharmaceuticals, Syndax, Synthorx, Stemline Therapeutics, Taiho Pharmaceutical, Takea, TopAlliance Biosciences Inc, Vedanta Biosciences, Verastem, Vigeo Therapeutics, xencor, Artios, Treadwell Therapeutics, MadSpace Biosciences, IgM Biosciences, Puretech, Erasca Inc. G.S. Falchook: Financial Interests, Institutional, Advisory Board: FujiFilm, Silicon, Navire, Turning Point, Predicine, Inspirna, Regeneron; Financial Interests, Personal, Advisory Board: EMD Serono; Financial Interests, Personal, Invited Speaker: Total Health Conferencing, 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, for work and/or research related to institution, 2018: Fujifilm; Financial Interests, Personal, Other, Travel, for work and/or research related to institution, 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, Royalties: Wolters Kluwer; Financial Interests, Institutional, Invited Speaker: 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, Black Diamond, Boehringer Ingelheim, Celldex, Celgene, Ciclomed, Daiichi, Curegenix, Curis, Cyteir, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Epizyme, Erasca, Exelixis, Freenome, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, IGM Biosciences, Ignyta, ImmunoGen/MarcoGenics, Incyte, Jacobio, Loxo/Bayer, Jounce, Jubilant, Kolltan, MedImmune, Millennium, Merck, miRNA Therapeutics, Molecular Templates, National Institutes of Health, Navire, NiKang, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Pyramid, Precision Oncology, Prelude, PureTech, RasCal, Regeneron, Relay, Rgenix, Ribon, Samumed, Sapience, Seagen, Silicon, Simcha, Sirnaomics, Strategia, Syndax, Synthorx/Sanofi, Taiho, Takeda, Tarveda, Teneobio, Tesaro, Tocagen, Turning Point, U.T. MD Anderson Cancer Center, Vegenics, Xencor. T. Koyama: Financial Interests, Personal, Speaker’s Bureau: Chugai, Sysmex; Financial Interests, Institutional, Research Grant: PACT Pharma. C.F. Friedman: Non-Financial Interests, Personal, Advisory Board, (LYNK-002), Compensation Waived: Merck; Non-Financial Interests, Personal, Advisory Board, (My Pathway), Compensation Waived: Genentech; Non-Financial Interests, Personal, Principal Investigator: Daiichi Sankyo, Bristol Myers Squibb, Genentech/Roche , Merck, AstraZeneca; Financial Interests, Personal, Other, Personal Fees: Arch Oncology, Bristol Myers Squibb. S. Piha-Paul: Other, Institutional, Other, Clinical Trial Research Support through Institution: AbbVie, Inc., ABM Therapeutics, Inc., Acepodia, Inc, Alkermes, Aminex Therapeutics, Amphivena Therapeutics, Inc., BioMarin Pharmaceutical, Inc, Boehringer Ingelheim, Bristol Myers Squib, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd, Cyclacel Pharmaceuticals, Daiichi Sankyo, Inc., Eli Lilly, ENB Therapeutics, Five Prime Therapeutics, F-Star Beta Limited, F-Star Therapeutics, Limited, Gene Quantum, Genmab A/S, Genmab A/S, Gilead Sciences, Inc., GlaxoSmithKline, Helix BioPharma Corp., HiberCell, Inc., Immunomedics, Inc., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd., Lytix Biopharma AS, Medimmune, LLC., Medivation, Inc., Merck Sharp and Dohme Corp., Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Phanes Therapeutics, Principia Biopharma, Inc., Puma Biotechnology, Inc., Purinomia Biotech, Inc., Rapt Therapeutics, Inc., Seattle Genetics, Silverback Therapeutics, Synlogic Therapeutics, Taiho Oncology, Tesaro, Inc., TransThera Bio, ZielBio, Inc., NCI/NIH P30CA016672 – Core Grant (CCSG Shared Resources); Non-Financial Interests, Institutional, Other, Clinical Trial Research Support through Institution: Curis, Inc.; Other, Institutional, Other, Consultant: CRC Oncology. M. Awad: Financial Interests, Personal, Advisory Role: Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, Maverick, Blueprint Medicine, Syndax, Ariad, Nektar, ArcherDX, Mirati, NextCure, Novartis, EMD Serono; Financial Interests, Institutional, Funding: AstraZeneca, Lilly, Genentech, Bristol-Myers Squibbb. D.R. Adkins: Financial Interests, Institutional, Funding: Pfizer, Eli Lilly, Merck, Celgene/Bristol-Myers Squibb, Novartis, AstraZeneca, Blueprint Medicines, Kura Oncology, Exelixis, Matrix Biomed, Aduro Biotech, CUE Biopharma, Cofactor Genomics, Shanghai Denovo, Hookipa, Debio, Adlai Nortye, Beigene, Conjupro, Epizyme, Gilead, ISA, Roche, Rubius, Immutep, Tizona, Vaccinex, Genmab, Boehringer Ingelheim; Financial Interests, Institutional, Principal Investigator: Pfizer, Eli Lilly, Merck, Celgene/Bristol-Myers Squibb, Novartis, AstraZeneca, Blueprint Medicines, Kura Oncology, Exelixis, Matrix Biomed, Aduro Biotech, CUE Biopharma, Cofactor Geonomics, Shanghai Denovo, Hookipa, Debio, Adlai Nortye, Beigene, Conjupro, Epizyme, Gilead, ISA, Rocher, Rubius, Immutep, Tizona, Genmab, Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Merck, CUE Biopharma, Blueprint Medicines, Exelixis, Immunitas, Kura Oncology, TargImmune, Therapeutics, TwoXAR, Vaccinex, Xilio Therapeutics, Boehringer Ingelheim. S. Takahashi: Financial Interests, Personal, Invited Speaker: MSD, Eisai, Daiichi Sankyo, Chugai, Ono Pharmaceutical, Taiho, Bristol Myers Squibb, Eli Lilly; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Institutional, Principal Investigator: Tiaho, Daiichi Sankyo, Novartis, Ono Pharmaceutical, Eisai, IQVIA, Bristol Myers Squibb, Bayer, AstraZeneca. S. Kadowaki: Financial Interests, Personal, Invited Speaker: Taiho, Eli Lilly, MSD, Ono, Daichi Sankyo, BMS, Bayer, Merck Serono, Eisai; Financial Interests, Institutional, Funding: Taiho, Eli Lilly, MSD, Ono, Daichi Sankyo, Chugai, Nobelpharma, Yansen. B. Cheng: Financial Interests, Institutional, Stocks/Shares: Daiichi-Sankyo; Financial Interests, Institutional, Funding: Daiichi-Sankyo. N. Ikeda, A. Laadem, N. Yoshizuka: Financial Interests, Institutional, Stocks/Shares: Daiichi-Sankyo; Financial Interests, Institutional, Full or part-time Employment: Daiichi-Sankyo. M. Qian: Financial Interests, Institutional, Full or part-time Employment: Daiichi Sankyo; Financial Interests, Institutional, Stocks/Shares: Daiichi Sankyo. O. Dosunmu: Financial Interests, Institutional, Full or part-time Employment: Sarah Cannon Research Institute; Financial Interests, Institutional, Stocks/Shares, in Parent Company -HCA: Sarah Cannon Research Institute. H. Arkenau: Financial Interests, Personal, Invited Speaker: Servier, Guardant; Financial Interests, Personal, Advisory Board: iOnctura, Beigene; Financial Interests, Institutional, Invited Speaker: multiple small and large Pharma/Biotechs. M.L. Johnson: Financial Interests, Institutional, Research Grant, Funding: AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAlta, Boehringer Ingelheim, Calithera Biosciences, Checkpoint Therapeutics, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gaurdant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchison MediPharma, IDEYA Biosciences, IGM Biosciences, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Pfizer, PMV Pharmaceuticals, RasCal Therapeutics, Regeneron Pharmaceuticals , Rely Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals / Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL, Y-mAbs Therapeutics; Financial Interests, Personal, Research Grant, Funding: Gritstone Oncology, Tizona Therapeutics; Financial Interests, Institutional, Other, Consulting: Amgen, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Checkpoint Therapeutics, CytomX Thyerapeutics, Daiichi Sankyo, EcoR1, Editas Medicine, Esai, EMD Serono, G1 Therapeutics, Genentech/Roche; Financial Interests, Institutional, : Genmab. All other authors have declared no conflicts of interest.

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

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.

Background

Tumour-infiltrating myeloid cells drive mCRPC growth and therapeutic resistance, in part through IL-23 and NRG1 secretion. Inhibition of myeloid infiltration by disrupting the CXCR2 receptor axis can reverse ENZA resistance in PC models. AZD5069 is a selective CXCR2 antagonist.

Methods

This Ph 1/2 multi-centre study evaluated the combination of AZD5069 and ENZA in pts with mCRPC, ECOG PS2, who had progressed on 1 novel anti-androgen therapy (NAAT). A Ph1 ‘3+3’ dose-escalation design evaluated AZD5069 at 40, 80, 120, 160, and 320 mg BD in combination with ENZA at 160 mg OD. The Ph2 expansion utilised Simon’s 2-stage design for 2 potential expansion arms. The primary objective in Ph1 was to establish the RP2Ds. The primary endpoint in Ph2 was composite response rate (PSA fall >50%, RECIST, or CTC conversion). Secondary endpoints included: PK, PD, radiologic PFS and OS.

Results

As of 10FEB2022, 21 DLT-evaluable pts were enrolled to the Ph1; 11 pts were enrolled in Ph2. Pts had 6 median prior lines of therapy. Since antitumour activity was observed at AZD5069 160 mg BD plus ENZA, this dose level was expanded. PK studies showed ENZA-induced CYP3A4 metabolism of AZD5069; AZD5069 was therefore escalated to 320mg BD. No DLT was observed in Ph1 or 2. The main G3-4 treatment emergent adverse events (>10%) was afebrile, uncomplicated neutropenia (Ph1: 11/21, Ph2: 4/11), an on-target effect of AZD5069. 3/21 response-evaluable pts had partial responses (PR) and 2/21 had stable disease (SD) lasting >6 months (mo) in Ph1. At AZD5069 80 mg BD, 1/3 pt had SD (16 mo); at 120 mg BD, 1/3 pt had PR (-31% by RECIST, PSA -89%, PFS: 11 mo); at 160 mg BD, 1/6 pt had PR (PSA -82%, -20% by RECIST, PFS: 8 mo) and 1/6 pt had SD (8 mo); and at 320 mg BD, 1/6 pt had PR (PSA -64%, PFS: 5 mo, ongoing). In the Ph2 expansion at the lower RP2D of AZD5069 160 mg BD plus ENZA, 1/11 pt had 33% PSA fall and another had SD (11 mo). All patients with PR/SD>6 mo previously progressed on ENZA.

Conclusions

The combination of AZD5069 and ENZA is tolerable and has antitumor activity in mCRPC. We provide clinical evidence for direct targeting of myeloid chemotaxis as a therapeutic strategy in mCRPC.

Clinical trial identification

NCT03177187.

Legal entity responsible for the study

Institute of Cancer Research.

Funding

AstraZeneca, Prostate Cancer Foundation, Prostate Cancer UK, National Institute of Health and Research Biomedical Research Centre. This academic sponsored study received enzalutamide from Astellas and AZD5069 from AstraZeneca.

Disclosure

A. Sharp: Non-Financial Interests, Principal Investigator, Clinical trial in progress: Astrazenica, Amgen, Nurix; Non-Financial Interests, Principal Investigator, Clinical trial in set up: Exelixis; Non-Financial Interests, Institutional, Product Samples, Access to IMP as a gift for research: AstraZenica; Other, Paid consultancy: D.E Research. U. Vogl: Financial Interests, Institutional, Advisory Board: Roche, Pfizer, Merck, Janssen; Financial Interests, Institutional, Invited Speaker: Astellas, Health Books; Financial Interests, Institutional, Expert Testimony: Janssen; Financial Interests, Personal, Advisory Board: Eli Lilly, Servier, Pfizer, Janssen, MSD, Bayer, BMS; Financial Interests, Personal, Invited Speaker: Samo. I. Colombo: Financial Interests, Institutional, Funding, Honoraria: AstraZeneca, GLAXOSMITHKLINE, Novartis; Financial Interests, Personal, Advisory Role: MSD Oncology; Financial Interests, Institutional, Funding: MSD, Bayer, Osmania Pharmaceutical AB; Financial Interests, Personal, Other: Tesario. A. Stathis: Financial Interests, Institutional, Expert Testimony: Bayer; Financial Interests, Institutional, Advisory Board: Janssen, roche, Eli Lilly; Financial Interests, Institutional, Invited Speaker: Pfizer, Merck, Roche, Novartis, ADC Therapeutics, AbbVie, Bayer, Philogen, Cellestia, AstraZeneca. S. Jain: Financial Interests, Personal, Invited Speaker: Astellas, AstraZeneca, Bayer, Boston Scientific, Janssen; Financial Interests, Personal and Institutional, Invited Speaker, Research consumables: Boston Scientific. F. Raynaud: Financial Interests, Institutional, Research Grant: Cancer Research UK; Financial Interests, Institutional, Royalties, Investigator Award For Abiraterone: Institute of Cancer Research. A. Alimonti: Financial Interests, Personal, Stocks/Shares: Oncosence; Financial Interests, Personal, Ownership Interest: Bottega Organica; Financial Interests, Personal, Royalties, US11235017B2No income yet: Altergon SA; Financial Interests, Institutional, Royalties, US11168134B2No income: Fondazione Per L'istituto Oncologico Di Ricerca (IOR); Financial Interests, Personal, Royalties, US9668961B2No income yet: ATRAHASIS Srl; Financial Interests, Institutional, Research Grant: Dompé Farmaceutici, IBSA Institut Biochimique. J.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Financial Interests, Institutional, Advisory Board: Harpoon; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, Crescendo Biologics; Non-Financial Interests, Principal Investigator: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Non-Financial Interests, Institutional, Product Samples: Daiichi, Bayer, Pfizer, Merck Serono, AstraZeneca, Harpoon, Sierra Oncology, Genentech/Roche, Sanofi Aventis, GlaxoSmithKline. All other authors have declared no conflicts of interest.