646P - Phase Ib/II study of ompenaclid (RGX-202-01), afirst-in-class oral inhibitor of the creatine transporter SLC6A8, in combination with FOLFIRI and bevacizumab (BEV) in RAS mutated (RASm) second-line (2L) advanced/metastatic colorectal cancer (mCRC)

Background

Creatine Kinase B (CKB) was identified as a driver of RASm mCRC. CKB generates ATP from phosphocreatine (PCr), which is imported by SLC6A8. Ompenaclid depletes PCr and ATP resulting in tumor cell apoptosis. In a phase 1a study, ompenaclid monotherapy showed objective anti-tumor activity in RASm mCRC without dose-limiting toxicities (DLTs).

Methods

Objectives of this ongoing phase 1b/2 study are evaluation of safety, PK/PD and efficacy of ompenaclid + FOLFIRI/BEV in 2L mCRC. Eligible pts had disease progression after a 1L oxaliplatin-containing regimen.

Results

Enrollment as of 28Apr2023, 35 pts (22 KRASm, 3 NRASm, 10 RAS-wt) in the Dose Escalation/Expansion cohorts receiving 2400mg BID (n=14) or 3000mg BID (n=21); all pts received FOLFIRI/BEV. No DLTs were observed in Dose Escalation and a MTD was not reached. Across safety-evaluable pts (n=33), the most common treatment emergent AEs Gr≤2 were nausea (50%), diarrhea (44%); Gr≥3 were neutropenia (15%), abdominal pain (11%), diarrhea (11%), fatigue (11%). The AE profile is similar to FOLFIRI/BEV alone, demonstrating good combinability. At both ompenaclid doses, systemic exposure was comparable and resulted in up to a 48X increase in urine creatine, suggesting robust target inhibition. The ORR in 17 RASm and 10 RAS-wt evaluable pts was 41% (6 confirmed PRs, 1 unconfirmed PR) and 20% (2 unconfirmed PRs), respectively. Five RASm pts are pending 1st scan and not yet evaluable. PRs were observed in pts with diverse KRASm (G13D [2 pts], G12V [2 pts], G12D, G12S and pG10dup). For RASm pts, mPFS was 11.8M and mOS was 19.1M, and for RAS-wt pts, mPFS was 7.5M and mOS was 14.5M.

Conclusions

At the evaluated dose levels, ompenaclid + FOLFIRI/BEV was well tolerated and induced potent inhibition of the target SLC6A8. Encouraging efficacy was observed in pts with RASm mCRC, with a response rate exceeding that expected with SOC. This preferential RASm activity is consistent with preclinical and phase 1a data. There is a high unmet need for a safe and combinable oral pan-RASm therapy in mCRC. Recruitment of RASm pts continues and a randomized controlled trial in 2L RASm 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.

Disclosure

D.R. Spigel: Financial Interests, Institutional, Other, Consulting: Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Curio Science, EMD Serono, Evidera, Exelixis, Genentech/Roche, GSK, Intellisphere, Ipsen Biopharmaceuticals, Janssen, Jazz Pharmaceuticals, Lilly, Mirati Therapeutics, Molecular Templates, Monte Rosa Therapeutics, Novartis, Pfizer, Puma Biotechnology, Regeneron, Sanofi-Aventis; Financial Interests, Institutional, Research Grant, Serve as PI: Amgen, Aeglea Biotherapeutics, Agios, Bayer, Arrys Therapeutics, Astellas, AstraZeneca, BeiGene, BIND Therapeutics, Blueprint Medicine, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celldex Therapeutics, Clovis, Daiichi Sankyo, Eisai, Lilly, EMD Serono, Genentech/Roche, G1 Therapeutics, Gilead Sciences, ImClone Systems, GSK, GRAIL, Hutchinson MediPharma, Ipsen, Janssen, Loxo, MacroGenics, MedImmune, Merck, Nektar, PTC Therapeutics, Neon Therapeutics, Novartis, Novocure, Rgenix, SeaGen, Taiho Oncology, Tarveda, Verastem, Tizona Therapeutics, Transgene, UT Southwestern, Arcus Biosciences, Oncologie, 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. M. Fakih: Financial Interests, Personal, Advisory Role: AstraZeneca, Bayer Corporation, Bristol Myers Squibb, Eisai Oncology, Entos, Merck, Roche/Genentech; Financial Interests, Personal, Advisory Board: Mirati, Nouscom; Financial Interests, Institutional, Research Grant: Genentech, Verastem. A.S. Paulson: Financial Interests, Personal, Invited Speaker, Medical education, non-branded, industry sponsored: Ideo Oncology; Financial Interests, Personal, Advisory Board: Amgen, Bristol Myers Squibb, Eisai, Ipsen, Incyte, Exelixis, AAA, Pfizer, QED, Lilly, Mirati, Hutchinson, Astellas; Financial Interests, Personal, Stocks/Shares: Alexion, Actinium, Aptose; Financial Interests, Invited Speaker: Ipsen, Hutchinson, Bristol Myers Squibb, Exelixis, Hutchinson med, Taiho, Lilly, AstraZeneca, Incyte, Seattle Genetics, Deciphera, Tempus, Zentalis, G1 therapeutics, Merck, Camurus, Novartis, Surface, Relay Therapeutics; Financial Interests, Institutional, Invited Speaker: Mirati, Bayer. R. Wasserman: Financial Interests, Personal, Advisory Board: Secotral Asset Management, Sixty Degree; Financial Interests, Personal, Officer: Inspirna; Financial Interests, Personal, Stocks/Shares: Inspirna, Sectoral Asset Management, Sixty Degree, Northern Biologics, Thatch Health; Financial Interests, Personal, Invited Speaker: Inspirna; Financial Interests, Personal, Royalties: Northern Biologics. All other authors have declared no conflicts of interest.