600TiP - A randomized blinded phase II study of ompenaclid (RGX-202-01) vs placebo in combination with FOLFIRI plus bevacizumab (BEV) in patients (pts) with previously treated RAS mutated (RASmt) advanced/metastatic colorectal cancer (mCRC)

Background

Pts with RASmt mCRC have a short median progression-free survival (PFS) of ∼5–6 months and median overall survival (OS) of ∼1 year after failing first-line (1L) therapy. Novel therapies with modes of action distinct from these established agents are urgently needed to improve on patient outcomes. Creatine metabolism was found to be activated in RASmt mCRC as a mechanism to fuel the increased energy demands of RASmt tumors. Ompenaclid is a first-in-class small molecule inhibitor of the creatine transporter SLC6A8 that prevents import of creatine and the high energy metabolite phosphocreatine, which results in depletion of intracellular ATP levels, leading to tumor cell apoptosis. In an open-label single arm study (RGX-202-001) as 2L treatment in pts with RASmt mCRC, ompenaclid at 2400 mg and 3000 mg orally twice-daily (BID) in combination with FOLFIRI/BEV was shown to have potential clinical benefit with a tolerable safety profile (ESMO 2023, abstract 646P).

Trial design

Key eligibility criteria: measurable disease per RECIST v1.1, disease progression after 1L oxaliplatin-based therapy and ECOG performance status 0–1. Treatment consists of FOLFIRI/BEV (irinotecan intravenously [IV] 180 mg/m², 5-FU 46-hour IV 2400 mg/m², leucovorin IV 400 mg/m², BEV IV 5 mg/kg every 2 weeks), with double-blind 1:1 randomization to either ompenaclid 3000 mg PO BID or placebo, stratified by prior exposure to 1L BEV. Treatment will continue until disease progression or unacceptable toxicity. Tumor assessment will be performed every 8 weeks. The primary end point is overall response rate. Secondary endpoints include PFS, OS, safety and tolerability. The study will enroll 70 pts and is conducted in Spain, Belgium and France. Study enrollment is ongoing.

Clinical trial identification

NCT05983367; EudraCT 2023-503356-27-00.

Editorial acknowledgement

Lesley Skingley, Bexon Clinical Consulting.

Legal entity responsible for the study

Inspirna, Inc.

Funding

Inspirna, Inc. and Merck KGaA, Darmstadt, Germany.

Disclosure

M.E. Elez Fernandez: Financial Interests, Personal, Advisory Board: Hoffman La - Roche, Servier, Amgen, Merck Serono, Sanofi, Bayer, Pierre Fabre, MSD, Takeda, Boehringer Ingelheim, Cure Teq AG, Repare Therapeutics Inc., RIN Institute Inc., Janssen; Financial Interests, Personal, Invited Speaker: Organon, Novartis, Pfizer, BMS, Lilly, Medscape; Financial Interests, Personal, Other, Educational training: Seagen International GmbH; Financial Interests, Institutional, Funding: Hoffmann-La Roche Ltd, Sanofi Aventis Recherche & Développement, Amgen Inc., Boehringer Ingelheim, Novartis Farmacéutica SA, Bristol-Myers Squibb International Corporation, BeiGene, HalioDX SAS, Janssen-Cilag SA, Merck Health KGAA, Merck Sharp & Dohme de España SA, PharmaMar SA, Servier, Taiho Pharma USA Inc, Hutchison MediPharma International, Menarini, Merus NV, Pfizer, Mirati, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, Celgene International SARL, Debiopharm International SA, Genentech Inc, MedImmune, Abbvie Deutschland Gmbh & Co KG, Bayer Pharma AG, Bioncotech Therapeutics, S.L., Biontech Rna Pharmacuticals GMBH, Biontech Small Molecules GMBH, Boehringer Ingelheim de España S.A., Daiichi Sankyo, Inc, Gercor, Hutchinson Medipharma Limited, Iovance Biotherapeutics, Inc., Janssen Research & Development, Menarini Ricerche SPA, Merck, Sharp & Dohme De España S.A., Nouscom SRL., Pledpharma AB, Redx Pharma PLC, Scandion Oncology, Seattle Genetics Inc., Sotio A.S., Wntresearch AB; Non-Financial Interests, Other, Coordinator of the SEOM +MIR Section of Residents and Young Assistants: Sociedad Española de Oncología Médica (SEOM); Non-Financial Interests, Other, Speaker of the ESMO Academy: European Society for Medical Oncology (ESMO); Non-Financial Interests, Other, Volunteer member of the ASCO Annual Meeting Scientific Program Committee: Developmental Therapeutics – Immunotherapy: American Society of Clinical Oncology (ASCO); Non-Financial Interests, Leadership Role, Member of the Scientific Program Committee and Developmental Therapeutics-Immunotherapy Track Leader, 2023-2024 term: American Society for Clinical Oncology (ASCO); Non-Financial Interests, Other, Member of the Scientific Committee 2024: European Society for Medical Oncology (ESMO); Other, Travel, Accommodations, Expenses: Roche, Merck Serono, Sanofi, Amgen, Array BioPharma, Servier, Bristol-Myers Squibb. S. Rosello Keranen: Financial Interests, Personal, Advisory Board: Pierre Fabre, Servier, Sirtex, Amgen; Financial Interests, Personal, Invited Speaker: Servier, MSD, Amgen; Financial Interests, Institutional, Local PI: Novartis, Roche, Pfizer, Pierre Fabre, Astellas, Seagen, Menarini, Hutchinson, Mirati, G1 Therapeutics, Ability Pharmaceuticals. D. Paez: Financial Interests, Personal, Invited Speaker: MSD, Novartis, BMS; Financial Interests, Personal, Advisory Board: Amgen, Esteve, Ipsen; Financial Interests, Personal and Institutional, Research Grant: Merck. J. Jiménez Castro: Financial Interests, Personal, Other, Honoraria/Travel expenses; congress support: Servier; Financial Interests, Personal, Other, Honoraria: Merck; Financial Interests, Personal, Other, Travel expenses/Congress support: Amgen. F. Rivera Herrero: Financial Interests, Personal, Invited Speaker: Roche, MSD, BMS, Servier, Astellas, Amgen, Merck; Financial Interests, Personal, Advisory Board: MSD, BMS, Servier, Astellas, Amgen, AstraZeneca; Financial Interests, Institutional, Local PI: AstraZeneca, MSD, Novartis, Seagen, OBT, Inspirna. A. Ruiz-Casado: Financial Interests, Personal, Invited Speaker: Servier, Abbott, Nestle, Medtronic; Financial Interests, Personal, Advisory Board: Pierre Fabre, Amgen. C. Montagut Viladot: Financial Interests, Personal, Advisory Board: Merck Serono, Roche; Financial Interests, Personal, Invited Speaker: Merck Serono, Pierre Fabre, Guardant Health, Amgen; Financial Interests, Institutional, Royalties: Biocartis; Financial Interests, Institutional, Coordinating PI: Merck-Serono; Non-Financial Interests, Member: TTD (Grupo Tratamiento Tumores Digestivos). M.P. Ducreux: Financial Interests, Personal, Invited Speaker: Roche, Amgen, Pierre Fabre, Merck Kga, Pfizer, Bayer, Lilly, Servier, MSD, BeiGene; Financial Interests, Personal, Advisory Board: Roche, Basilea, Pierre Fabre, Boehringer, Rafael, Servier, Zymeworks, Ipsen, Bayer, HalioDX, Lilly, GSK, Daiichi Sankyo, MSD, Servier, BeiGene; Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Funding, Partial funding of a trial evaluating the role of bevacizumab in NET: Roche; Financial Interests, Institutional, Funding, Partial funding of a trial evaluating the role of Steptozotocin in NET: Keocyt; Financial Interests, Institutional, Local PI: Rafael, Amgen; Financial Interests, Institutional, Funding: Bayer; Other, My wife is head of the oncology business unit in the French Affiliate of Sandoz: Sandoz France. H. Prenen: Financial Interests, Institutional, Advisory Board: Amgen, Roche, AstraZeneca; Financial Interests, Institutional, Invited Speaker: Bayer, Ipsen, Sanofi. P. Cuyle: Financial Interests, Personal, Advisory Board: MSD, Lilly, Amgen, Pierre Fabre, Novartis, Servier, Roche/Genentech; Financial Interests, Personal, Invited Speaker: IPSEN, Merck; Financial Interests, Institutional, Local PI: Boehringer Ingelheim, Abbvie, Astellas, Roche, Array, Pfizer, BioNTech, Boston, BMS, MSD, Servier, Inspirna Inc, Actuate Therapeutics, Novartis, Panbela Therapeutics, Lilly, BeiGene, Zymeworks, Jazz Pharma, Armo Biosciences, AstraZeneca, Daiichi-Sankyo, Cantargia, Halozyme, Erytech Pharma. J. Raimbourg: Financial Interests, Institutional, Invited Speaker: AstraZeneca, Pierre Fabre, Amgen, Sanofi; Financial Interests, Institutional, Advisory Board: Takeda, Bms, Merck. N. Bechar: Financial Interests, Personal, Full or part-time Employment, I am the VP of clinical development at Inspirna Inc.: Inspirna INC.; Financial Interests, Personal, Stocks/Shares: Inspirna Inc. J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, AstraZeneca, Boehringer Ingelheim, Chugai, Daichii Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc., Ikena Oncology, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Scandion Oncology, Ona Therapeutics, Sotio Biotech, Inspirna Inc, Scorpion Therapeutics, Tolremo Therapeutics, CARSgen Therapeutics, hC Bioscience Inc, Takeda Pharmaceuticals International AG, Alentis Therapeutics, Immodulon Therapeutics; Financial Interests, Personal, Invited Speaker, educational collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex / HMP; Financial Interests, Personal, Advisory Board: Cardiff Oncology, Aveo Oncology; Financial Interests, Personal, Stocks/Shares: Oniria Therapeuics, 1TRIALSP, Alentis Therapeutics, Pangaea Oncology; Financial Interests, Institutional, Research Grant, ACRCelerate: Colorectal Cancer Stratified: Fundación Científica de la Asociación Española Contra el Cáncer; Financial Interests, Institutional, Research Grant, OPTIMISTICC: Opportunity to Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer: Cancer Research UK; Financial Interests, Institutional, Funding, Clinical Trials & Research: Amgen Inc, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, Janssen-Cilag International NV, Merck Health KGAA, Merck, Sharp & Dohme de España, SA, Novartis Farmacéutica SA, PharmaMar SA, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA, Inc, BeiGene, Boehringer Ingelheim, Menarini, Merus N V, Pfizer, Mirati; Non-Financial Interests, Member of Board of Directors, Board of Directors: Cancer Core Europe, Spanish Association Against Cancer -AECC; Non-Financial Interests, Member of Board of Directors, General Assembly: Horizon Europe Cancer Mission; Non-Financial Interests, Leadership Role, External Scientific Committee: Institute for Health Research INCLIVA – Clinical Hospital of Valencia, IdiSNA –Universidad de Navarra; Non-Financial Interests, Leadership Role, Scientific Advisory Board: Spanish National Cancer Research Centre (CNIO); Non-Financial Interests, Advisory Role, International Scientific Evaluation Committee: Bosch Health Campus (BHC); Non-Financial Interests, Advisory Role, Review Board: National Decade Against Cancer (NCT) - German Consortium for Translational Cancer Research (DKTK); Non-Financial Interests, Advisory Role, Scientific Advisory Board: Karolinska Comprehensive Cancer Centre; Non-Financial Interests, Advisory Role, International Review Committee (IRC): Oncode Institute; Non-Financial Interests, Advisory Role, Scientific Advisory Board (SAB): Oslo University Hospital Comprehensive Cancer Centre (OUH CCC); Non-Financial Interests, Leadership Role, Governance Advisory Committee: European Organization for Research and Treatment of Cancer -EORTC; Non-Financial Interests, Leadership Role, Vice Chairman: World Innovative Networking (WIN) Consortium in Personalized Cancer Medicine; Non-Financial Interests, Other, Coordinating PI & Steering Committee Member. Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutical LP, Boehringer Ingelheim, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Pfizer, Servier; Non-Financial Interests, Principal Investigator, Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutics LP, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc; Non-Financial Interests, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, Merus NV, Taiho Pharma USA Inc; Non-Financial Interests, Other, Coordinating PI. Clinical Trials & Research: Mirati; Non-Financial Interests, Member: AACR, ASCO, EACR, EORTC, SEOM; Other, President: Oncology Master Plan – Catalonia Department of Health; Other, Advisory Committee: Advisory Committee on Pharmaceutical Provision Financing under the Spanish National Health System. All other authors have declared no conflicts of interest.