575P - Phase Ib/II study of ompenaclid (RGX-202-01), a first-in-class oral inhibitor of the creatine transporter SLC6A8, in combination with FOLFIRI and bevacizumab (BEV) in RAS mutated (RASmt) second-line (2L) advanced/metastatic colorectal cancer (mCRC): Updated results

Background

RASmt CRC overexpresses Creatine Kinase B (CKB) to generate phosphocreatine (PCr) as an energy source to fuel high metabolic demands. PCr is imported by SLC6A8 and its import is inhibited by ompenaclid, resulting in cancer cell death through depletion of intracellular PCr and ATP levels. This abstract presents updated efficacy and safety data from ESMO 2023 (abstract 646P).

Methods

This is an ongoing Ph 1b/2 study evaluating ompenaclid + FOLFIRI/BEV in 2L mCRC. Pts must have had progression after a 1L oxaliplatin-containing regimen. Outcomes include safety, PK/PD and efficacy.

Results

Enrollment into Dose Escalation/Expansion cohorts is complete; recruitment into a food-effect sub-study is ongoing. As of 10Apr2024, 51 pts have been treated (37 KRASmt, 5 NRASmt, 9 RASwt) with ompenaclid 2400 or 3000 mg BID in combination with FOLFIRI/BEV; 7 pts with RASmt remain on treatment. The ORR in RASmt and RASwt evaluable pts was 41% and 22%, all PRs, respectively. In RASmt pts, ORR was higher and mPFS was longer in BEV-naïve vs prior BEV-treated pts. PRs were observed in pts with diverse RASmt including NRAS. Table: 575P

a. Had post-baseline scan and received 70% of planned doses during first cycle BEV=bevacizumab; ITT=intent-to-treat; NR=median not reached; ORR=overall response rate; OS=overall survival; PD=progressive disease; PFS=progression-free survival

The most common treatment-emergent AEs Gr≤2 were diarrhea (59%), nausea (53%), fatigue (45%); Gr≥3 were neutropenia (22%), diarrhea (12%), fatigue (10%). The AE profile appears similar to that known from FOLFIRI/BEV alone, demonstrating good combinability.

Conclusions

Ompenaclid + FOLFIRI/BEV was well tolerated. Encouraging efficacy was observed in pts with RASmt mCRC, with ORR, mPFS and mOS exceeding that expected with standard of care. This preferential RASmt activity is consistent with preclinical and Ph 1a data. There is a high unmet need for a combinable oral pan-RASmt therapy in mCRC. A randomized trial in 2L RASmt mCRC is ongoing, and a dose-escalation/expansion study of ompenaclid + FOLFOX/BEV in 1L RASmt mCRC is planned.

Clinical trial identification

NCT03597581.

Editorial acknowledgement

Lesley Skingley, Bexon Clinical Consulting.

Legal entity responsible for the study

Inspirna, Inc.

Funding

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

Disclosure

A. Hendifar: Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Institutional, Local PI: Merck, Pfizer, Faeth, cantex, inspirna, elicio; Financial Interests, Personal, Other, I am on the DSMC: rayzebio; Non-Financial Interests, Advisory Role, SMAB: PANCAN. J. Gong: Financial Interests, Personal, Advisory Board: Astellas, QED Therapeutics, Exelixis, Amgen, AVEO, Basilea Pharmaceutical, EMD Serono, HalioDx, Janssen Biotech, Natera, Bayer, Pfizer/Myovant, Incyte, Eisai, Seagen; Financial Interests, Personal, Writing Engagement: Elsevier; Financial Interests, Personal, Invited Speaker: OncLive/MJH Life Sciences. D.R. Spigel: Financial Interests, Institutional, Other, Consulting: AstraZeneca, BeiGene, Bristol-Myers Squibb, Evidera, GSK, Ipsen Biopharmaceuticals, Janssen, Jazz Pharmaceuticals, Lilly, Molecular Templates, Monte Rosa Therapeutics, Novartis, Pfizer, Regeneron, Sanofi-Aventis, Abbvie, Novocure, Roche/Genentech; Financial Interests, Institutional, Research Grant, Serve as PI: Amgen, Aeglea Biotherapeutics, Agios, Arrys Therapeutics, Astellas, AstraZeneca, Bayer, BeiGene, BIND Therapeutics, Blueprint Medicine, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celldex Therapeutics, Clovis, Daiichi Sankyo, Eisai, Lilly, Genentech/Roche, G1 Therapeutics, Gilead Sciences, GSK, GRAIL, Hutchinson MediPharma, ImClone Systems, Ipsen, Janssen, Loxo, MacroGenics, MedImmune, Merck, Nektar, Neon Therapeutics, Novartis, Novocure, Rgenix, SeaGen, Taiho Oncology, Tarveda, Tizona Therapeutics, Transgene, UT Southwestern, Verastem, Arcus Biosciences, Molecular Template, Cyteir Therapeutics, BioNTech, Apollomics, Pure Tech Health, Elevation Oncology, Repare Therapeutics, Razor Genomics, Denovo Biopharma, Erasca, Kronos Bio, Zai Laboratory, Faeth Therapeutics, Ascendis Pharma, Lyell Immunopharma, Synthekine, Shenzhen Chipscreen Biosciences, Abbvie, AnHeart Therapeutics, Calithera, Endeavor, FujiFilm Pharmaceuticals, Incyte, Jazz Pharmaceuticals, Millennium Pharmaceuticals, Moderna, Monte Rosa Therapeutics, Peloton Therapeutics, Stemline Therapeutics, Tango Therapeutics, Tesaro. M. Fakih: Financial Interests, Personal, Advisory Board, Consultant: AbbVie, Inc., AstraZeneca, Bayer Corporation; Financial Interests, Personal, Advisory Board, Consultant/One Meeting: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, One meeting: Eisai Oncology; Financial Interests, Personal, Advisory Board, One meeting: Entos, Seattle Genetics, Xenthera; Financial Interests, Personal, Advisory Board, One Meeting: Janssen; Financial Interests, Personal, Advisory Board: Merck, Nouscom, Roche / Genentech; Financial Interests, Personal, Advisory Board, Also Editorial Boards & Consulting: Mirati Therapeutics; Financial Interests, Personal, Advisory Board, Consulting/One Meeting: Pfizer; Financial Interests, Personal, Advisory Board, Consulting: Taiho Oncology; Financial Interests, Institutional, Research Grant: AgenusBio, Genentech / imCORE, Verastem. A.S. Paulson: Financial Interests, Personal, Stocks or ownership: Actinium; Financial Interests, Personal, Other, Honoraria: Cardinal Health, Curio Science, Array BioPharma; Financial Interests, Personal, Advisory Board: Amgen, Bristol Myers Squibb, Eisai, Ipsen, Advanced Accelerator Applications, Incyte, Exelixis, Pfizer, QED Therapeutics, Lilly Pharmaceuticals, Mirati, Hutchinson, Astellas Pharma, AADi, Stromatis Pharma, EMD Serono, AstraZeneca, SERVIER, Novartis, Array BioPharma, Bayer, Jazz Pharmaceuticals, Takeda, Seagen, Agenus; Financial Interests, Personal, Speaker’s Bureau: Ideo Oncology; Financial Interests, Personal, Research Funding: Buzzard Pharmaceuticals; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Pfizer, Camurus, Mirati Therapeutics, Nucana, AADi; Financial Interests, Institutional, Research Funding: Ipsen, Bristol Myers Squibb, Exelixis, Hutchinson, Taiho Pharmaceutical, Lilly, AstraZeneca, Incyte, Deciphera, G1 Therapeutics, Zentalis, Tempus, Camurus, Relay Therapeutics, Nucana, Merck, Bayer, Seattle Genetics, Sotio, Innovative Cellular Therapeutics Co, Regenxbio, Gilead Sciences, Gritstone Bio, BioNTech SE, Novartis, TransThera Biosciences, ITM Oncologics, Inspirna. N. Bechar: Financial Interests, Personal, Full or part-time Employment, I am the VP of clinical development at Inspiran Inc.: Inspirna INC.; Financial Interests, Personal, Stocks/Shares: inspirna Inc. K.A. Hoffman: Financial Interests, Personal, Full or part-time Employment: Inspirna, Inc. S. Spector: Financial Interests, Personal, Project Lead: Inspirna, Inc. M. Szarek: Financial Interests, Personal, Full or part-time Employment: Inspirna, Inc. R. Wasserman: Financial Interests, Personal, Advisory Board: Secotral Asset Management, Sixty Degree, Inspirna; Financial Interests, Personal, Officer: Inspirna; Financial Interests, Personal, Stocks/Shares: Inspirna, Sectoral Asset Management, Sixty Degree, Northern Biologics, Thatch Health; Financial Interests, Personal, Royalties: Northern Biologics. L.S. Rosen: Financial Interests, Institutional, Funding, PI at UCLA Health Hem/Onc for Inspirna trial. Institution receives research funding from Inspirna: Inspirna. All other authors have declared no conflicts of interest.