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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| RMC-9805 monotherapy arm | Experimental | Dose exploration and dose expansion |
|
| RMC-9805 plus RMC-6236 combination arm | Experimental | Dose exploration and dose expansion |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| RMC-9805 | Drug | Oral Tablets |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 | Up to 3 years |
| Dose Limiting Toxicities | Number of participants with Dose Limiting Toxicities (DLTs) | 21 days |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | Cmax | 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 |
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Inclusion Criteria:
Exclusion Criteria:
Other inclusion/exclusion criteria may apply.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Revolution Medicines, Inc. | Contact | 1-844-2-REVMED | medinfo@RevMed.com |
| Name | Affiliation | Role |
|---|---|---|
| Revolution Medicines, Inc. | Revolution Medicines, Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California, Davis Comprehensive Cancer Center | Recruiting | Sacramento | California | 95817 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40705880 | Derived | 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. | |
| 40056080 |
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The monotherapy arm of RMC-9805; the combination arm of RMC-9805 plus RMC-6236
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| RMC-6236 | Drug | Oral Tablets |
|
Tmax |
| 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 | AUC | 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 | accumulation ratio | 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 | t1/2 | up to 21 weeks |
| Overall Response Rate (ORR) | Assess per RECIST v1.1 | up to 3 years |
| Duration of Response (DOR) | Assess per RECIST v1.1 | up to 3 years |
| Disease Control Rate (DCR) | Assess per RECIST v1.1 | up to 3 years |
| Time to Response (TTR) | Assess per RECIST v1.1 | up to 3 years |
| Progression-Free Survival (PFS) | Assess per RECIST v1.1 | up to 3 years |
| Smilow Cancer Hospital (Yale University) | Recruiting | New Haven | Connecticut | 06511 | United States |
| Florida Cancer Specialists | Recruiting | Sarasota | Florida | 34232 | United States |
| Lee Moffitt Cancer Center | Recruiting | Tampa | Florida | 33612 | United States |
| Johns Hopkins University | Recruiting | Baltimore | Maryland | 21287 | United States |
| Massachusetts General Hospital | Recruiting | Boston | Massachusetts | 02114 | United States |
| Dana-Farber Cancer Institute | Recruiting | Boston | Massachusetts | 02215 | United States |
| NYU Langone | Recruiting | New York | New York | 10016 | United States |
| Memorial Sloan Kettering Cancer Center | Recruiting | New York | New York | 10065 | United States |
| Duke Cancer Center | Recruiting | Durham | North Carolina | 27710 | United States |
| Carolina BioOncology Institute | Recruiting | Huntersville | North Carolina | 28078 | United States |
| The Christ Hospital | Recruiting | Cincinnati | Ohio | 45219 | United States |
| Sarah Cannon Research Institute | Recruiting | Nashville | Tennessee | 37203 | United States |
| Sarah Cannon Research Institute at Mary Crowley | Recruiting | Dallas | Texas | 75230 | United States |
| University of Texas, MD Anderson Cancer Center | Recruiting | Houston | Texas | 77030 | United States |
| START | Recruiting | San Antonio | Texas | 78229 | United States |
| NEXT Oncology Virginia | Recruiting | Fairfax | Virginia | 22031 | United States |
| Derived |
| 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. |
| ID | Term |
|---|---|
| D002289 | Carcinoma, Non-Small-Cell Lung |
| D015179 | Colorectal Neoplasms |
| D008175 | Lung Neoplasms |
| D003110 | Colonic Neoplasms |
| D010190 | Pancreatic Neoplasms |
| D009362 | Neoplasm Metastasis |
| D005770 | Gastrointestinal Neoplasms |
| ID | Term |
|---|---|
| D002283 | Carcinoma, Bronchogenic |
| D001984 | Bronchial Neoplasms |
| D012142 | Respiratory Tract Neoplasms |
| D013899 | Thoracic Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D007414 | Intestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D003108 | Colonic Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |
| D004701 | Endocrine Gland Neoplasms |
| D010182 | Pancreatic Diseases |
| D004700 | Endocrine System Diseases |
| D009385 | Neoplastic Processes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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