451O - Preliminary evidence of clinical activity from phase I and Ib trials of the CLK/DYRK inhibitor cirtuvivint (CIRT) in subjects with advanced solid tumors

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.

Editorial acknowledgement

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.