RecruitingInterventionalPhase 1

Phase 1/1b, Multicenter, Open-Label, Study of RMC 9805 in Participants With Advanced KRASG 12D-Mutant Solid Tumors

NCT ID: NCT06040541Sponsor: Revolution Medicines, Inc.Last updated: 2026-06-03

Summary

This study is to evaluate the safety and tolerability of RMC-9805 as monotherapy and in combination with RMC-6236 in adults with KRAS G12D-mutant solid tumors.

Detailed description

This is an open-label, multicenter, Phase 1/1b study of RMC-9805, a selective and orally bioavailable KRAS G12D(ON) inhibitor, in subjects with KRASG12D-mutant solid tumors to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary clinical activity. The study consists of two arms: RMC-9805 monotherapy arm and RMC-9805 plus RMC-6236 combination arm. Both arms consist of two parts: Part 1- dose exploration and Part 2- dose expansion.

Arms & interventions

DrugRMC-9805
Oral Tablets
DrugRMC-6236
Oral Tablets

Outcome measures

Primary

Adverse events
Incidence and severity of treatment-emergent Adverse Events (AEs) and serious AEs and clinically significant changes in laboratory values, ECGs, and vital signs
Time frame: Up to 3 years
Dose Limiting Toxicities
Number of participants with Dose Limiting Toxicities (DLTs)
Time frame: 21 days

Secondary

Maximum Observed Blood Concentration (Cmax) of RMC-9805 as monotherapy and in combination with RMC-6236, and Cmax of RMC-6236 in combination with RMC-9805
Time frame: up to 21 weeks
Time to Reach Maximum Blood Concentration (Tmax) of RMC-9805 as monotherapy and in combination with RMC-6236, and Tmax of RMC-6236 in combination with RMC-9805
Time frame: up to 21 weeks
Area Under Blood Concentration Time Curve (AUC) of RMC-9805 as monotherapy and in combination with RMC-6236, and AUC of RMC-6236 in combination with RMC-9805
Time frame: up to 21 weeks
Ratio of accumulation of RMC-9805 from a single dose to steady state with repeated dosing as monotherapy and in combination with RMC-6236, and ratio of accumulation of RMC-6236 in combination with RMC-9805
Time frame: up to 21 weeks
Elimination Half-Life (t1/2) of RMC-9805 as monotherapy and in combination with RMC-6236, and t1/2 of RMC-6236 in combination with RMC-9805
Time frame: up to 21 weeks
Overall Response Rate (ORR)
Time frame: up to 3 years
Duration of Response (DOR)
Time frame: up to 3 years
Disease Control Rate (DCR)
Time frame: up to 3 years
Time to Response (TTR)
Time frame: up to 3 years
Progression-Free Survival (PFS)
Time frame: up to 3 years

Eligibility criteria

Sex: AllAge: 18 Years and olderHealthy volunteers: No

Inclusion Criteria: * Pathologically documented, locally advanced or metastatic solid tumor with a KRAS G12D-mutation * Received and progressed or been intolerant to prior standard therapy (including targeted therapy) appropriate for tumor type and stage * ECOG performance status 0 or 1 * Adequate organ function Exclusion Criteria: * Primary central nervous system (CNS) tumors * Known or suspected leptomeningeal or active brain metastases or spinal cord compression * Known or suspected impairment of gastrointestinal function that may prohibit ability to swallow or absorb an oral medication * Participant was previously treated with an investigational KRAS G12D inhibitor, pan- or multi-RAS inhibitor, or had prior therapy with any direct RAS-targeted therapy (eg, degraders and inhibitors) Other inclusion/exclusion criteria may apply.

Study locations (17)

University of California, Davis Comprehensive Cancer Center

Sacramento, California, 95817

Recruiting

Smilow Cancer Hospital (Yale University)

New Haven, Connecticut, 06511

Recruiting

Florida Cancer Specialists

Sarasota, Florida, 34232

Recruiting

Lee Moffitt Cancer Center

Tampa, Florida, 33612

Recruiting

Johns Hopkins University

Baltimore, Maryland, 21287

Recruiting

Massachusetts General Hospital

Boston, Massachusetts, 02114

Recruiting

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215

Recruiting

NYU Langone

New York, New York, 10016

Recruiting

Memorial Sloan Kettering Cancer Center

New York, New York, 10065

Recruiting

Duke Cancer Center

Durham, North Carolina, 27710

Recruiting

Carolina BioOncology Institute

Huntersville, North Carolina, 28078

Recruiting

The Christ Hospital

Cincinnati, Ohio, 45219

Recruiting

Sarah Cannon Research Institute

Nashville, Tennessee, 37203

Recruiting

Sarah Cannon Research Institute at Mary Crowley

Dallas, Texas, 75230

Recruiting

University of Texas, MD Anderson Cancer Center

Houston, Texas, 77030

Recruiting

START

San Antonio, Texas, 78229

Recruiting

NEXT Oncology Virginia

Fairfax, Virginia, 22031

Recruiting

References

Weller C, Burnett GL, Jiang L, Chakraborty S, Zhang D, Vita NA, Dilly J, Kim E, Maldonato B, Seamon K, Eilerts DF, Milin A, Marquez A, Spradlin J, Helland C, Gould A, Ziv TB, Dinh P, Steele SL, Wang Z, Mu Y, Chugh S, Feng H, Hennessey C, Wang J, Roth J, Rees M, Ronan M, Wolpin BM, Hahn WC, Holderfield M, Wang Z, Koltun ES, Singh M, Gill AL, Smith JAM, Aguirre AJ, Jiang J, Knox JE, Wildes D. A neomorphic protein interface catalyzes covalent inhibition of RASG12D aspartic acid in tumors. Science. 2025 Jul 24;389(6758):eads0239. doi: 10.1126/science.ads0239. Epub 2025 Jul 24.(PubMed)
Cregg J, Edwards AV, Chang S, Lee BJ, Knox JE, Tomlinson ACA, Marquez A, Liu Y, Freilich R, Aay N, Wang Y, Jiang L, Jiang J, Wang Z, Flagella M, Wildes D, Smith JAM, Singh M, Wang Z, Gill AL, Koltun ES. Discovery of Daraxonrasib (RMC-6236), a Potent and Orally Bioavailable RAS(ON) Multi-selective, Noncovalent Tri-complex Inhibitor for the Treatment of Patients with Multiple RAS-Addicted Cancers. J Med Chem. 2025 Mar 27;68(6):6064-6083. doi: 10.1021/acs.jmedchem.4c02314. Epub 2025 Mar 8.(PubMed)