Study of RAS(ON) Inhibitors in Patients With Gastrointestinal Solid Tumors

A Platform Study of RAS(ON) Inhibitors in Patients With Gastrointestinal Solid Tumors

The purpose of this platform study is to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of novel RAS(ON) inhibitors combined with Standard(s) of Care (SOC) or with novel agents.

The current subprotocols include the following:

Subprotocol A: RMC-6236 + 5-fluorouracil-based regimens

Subprotocol B: RMC-6236 + cetuximab with or without mFOLFOX6

Subprotocol C: RMC-6236 + gemcitabine + nab-paclitaxel

Subprotocol D: RMC-9805 with or without RMC-6236 + 5-fluorouracil-based regimens

Subprotocol E: RMC-9805 with or without RMC-6236 + cetuximab with or without mFOLFOX6

Subprotocol F: RMC-9805 with or without RMC-6236 + gemcitabine + nab-paclitaxel

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; Pancreatic Ductal Adenocarcinoma; Gastrointestinal Cancer; CRC; Metastatic Pancreatic Ductal Adenocarcinoma; PDAC
• Intervention / Treatment: Drug: gemcitabine; Drug: nab-paclitaxel; Drug: bevacizumab; Drug: RMC-6236; Drug: mFOLFOX6 regimen; Drug: mFOLFIRINOX regimen; Drug: cetuximab; Drug: RMC-9805

Detailed Description

The platform study design allows combinations of RAS(ON) inhibitors with other anticancer agents to be evaluated in patients with RAS-mutated solid tumors with a focus on GI cancers.

This is an open-label platform study to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of novel RAS(ON) inhibitors combined with Standard of Care (SOC) or with novel agents, and to define the Recommended Phase 2 Dose and Schedule (RP2DS). Enrollment of patients with RAS mutations will be specified in each subprotocol.

Subprotocol A is an open-label, multicenter study of RMC-6236 in combination with 5-fluorouracil-based regimens in patients with treatment-naïve unresectable or metastatic colorectal cancer or treatment-naïve metastatic pancreatic ductal adenocarcinoma. Subprotocol B is an open-label, multicenter study of RMC-6236 in combination with cetuximab with or without mFOLFOX6 in patients with unresectable or metastatic colorectal cancer or patients with previously treated or treatment-naïve metastatic pancreatic ductal adenocarcinoma. Subprotocol C is an open-label, multicenter study of RMC-6236 in combination with gemcitabine and nab-paclitaxel in patients with treatment-naïve metastatic pancreatic ductal adenocarcinoma. Subprotocol D is an open-label, multicenter study of RMC-9805 with or without RMC-6236 in combination with 5-fluorouracil-based regimens in patients with RAS G12D-mutant unresectable or metastatic colorectal cancer or metastatic pancreatic ductal adenocarcinoma. Subprotocol E is an open-label, multicenter study of RMC-9805 with or without RMC-6236 in combination with cetuximab-based therapies with or without mFOLFOX6 in patients with RAS G12D-mutant unresectable or metastatic colorectal cancer or metastatic pancreatic ductal adenocarcinoma. Subprotocol F is an open-label, multicenter study of RMC-9805 with or without RMC-6236 in combination with gemcitabine and nab-paclitaxel in patients with RAS G12D-mutant metastatic pancreatic ductal adenocarcinoma.

Each subprotocol consists of two parts: Part 1 - Dose Exploration and Part 2 - Dose Expansion.

• Study Type: Interventional
• Enrollment (Estimated): 1130
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Revolution Medicines; Phone Number: 1-844-2-REVMED; Email: medinfo@revmed.com

Study Locations

• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Recruiting
      • Ironwood Cancer and Research Centers
      • Contact: Research Department; Phone Number: 480-398-7671; Email: research@ironwoodcrc.com
    • Phoenix, Arizona, United States, 85054
      • Recruiting
      • Mayo Clinic Hospital
      • Contact: Phone Number: 855-776-0015; Email: mayocliniccancerstudies@mayo.edu
    • Scottsdale, Arizona, United States, 85258
      • Recruiting
      • HonorHealth Research Institute
      • Contact: Andrea House; Phone Number: 480-323-1364; Email: ahouse@honorhealth.com
  • California
    • La Jolla, California, United States, 92093
      • Recruiting
      • UC San Diego Moores Cancer Center
      • Contact: Andrea Galfo; Phone Number: 858-822-4500; Email: agalfo@health.com
    • Los Angeles, California, United States, 90404
      • Recruiting
      • UCLA Hematology/Oncology- Santa Monica
      • Contact: Jenna Davis; Phone Number: 16128 (310) 633-8400; Email: jldavis@mednet.ucla.edu
    • Los Angeles, California, United States, 90048
      • Recruiting
      • Cedars-Sinai Cancer at Cedars-Sinai Medical Center
      • Contact: Naomi Geier; Phone Number: 310-423-4693; Email: naomi.geier@cshs.org
  • Colorado
    • Aurora, Colorado, United States, 88045
      • Recruiting
      • University of Colorado Hospital-Anschutz Cancer Pavilion
      • Contact: Emily Harper; Phone Number: (303) 724-9407; Email: Emily.harper@cuanschutz.edu
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Recruiting
      • Yale-New Haven Hospital-Yale Cancer Center
      • Contact: Kwasi Boateng; Phone Number: 203-314-7948; Email: Kwasi.Boateng@yale.edu
      • Contact: Stefanie Diaz; Phone Number: 475-227-1088; Email: Stefanie.Diaz@yale.edu
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Recruiting
      • Mayo Clinic Cancer Center
      • Contact: Phone Number: 855-776-0015; Email: mayocliniccancerstudies@mayo.edu
    • Tampa, Florida, United States, 33612
      • Recruiting
      • Moffitt Cancer Center
      • Contact: Nilufar Aliyeva; Phone Number: 813.745.4436; Email: Nilufar.Aliyeva@moffitt.org
  • Kansas
    • Westwood, Kansas, United States, 66205
      • Recruiting
      • The University of Kansas Clinical Research Center
      • Contact: Phone Number: 913-945-7552; Email: CTNurseNav@kumc.edu
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Recruiting
      • The Sidney Kimmel Comprehensive Cancer Center at John Hopkins
      • Contact: Joann Santmyer; Phone Number: 410-614-3644; Email: giclinicaltrials@jhmi.edu
      • Contact: Colleen Apostol; Phone Number: 410-614-3644; Email: giclinicaltrials@jhmi.edu
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Contact: Aparna Parikh; Phone Number: (617) 724-4000; Email: Aparna.Parikh@MGH.HARVARD.EDU
      • Contact: Bennett Caughey; Phone Number: (617) 724-4000; Email: bcaughey1@mgb.org
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana Farber Cancer Institute
      • Contact: Charlotte Healy; Phone Number: 617-632-5728; Email: charlotte_healy@dfci.harvard.edu
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic
      • Contact: Phone Number: 855-776-0015; Email: mayocliniccancerstudies@mayo.edu
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • Recruiting
      • University of Nebraska Medical Center
      • Contact: Mahdi Hassan; Phone Number: 402-559-1947; Email: mhassan@unmc.edu
      • Contact: Monica Davis; Phone Number: 402-559-9466; Email: mondavis@unmc.edu
    • Omaha, Nebraska, United States, 68130
      • Recruiting
      • Nebraska Cancer Specialists
      • Contact: Ashley Servais; Phone Number: 4029552691; Email: aservais@nebraskacancer.com
      • Contact: Evan Roberts; Phone Number: 4023344773; Email: eroberts@nebraskacancer.com
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Recruiting
      • Atlantic Health System
      • Contact: Salome Geene; Phone Number: 973-971-6373; Email: salome.geene@atlantichelath.org
      • Contact: Tracey Hilden; Phone Number: 973-971-7889; Email: tracey.hilden@atlantichealth.org
  • New York
    • Lake Success, New York, United States, 11042
      • Recruiting
      • Northwell Health / RJ Zuckerberg Cancer Center
      • Contact: Deeksha Kaura; Phone Number: 516-734-8906; Email: GITrialReferral@northwell.edu
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Medical Center
      • Contact: Phone Number: 212-342-5162; Email: cancerclinicaltrials@cumc.columbia.edu
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center Main Campus
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Recruiting
      • Duke University Medical Center
      • Contact: Brooke Currier; Phone Number: (919) 681-3933; Email: grayson.currier@duke.edu
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Recruiting
      • University of Cincinnati Medical Center
      • Contact: Phone Number: 513-584-7698; Email: cancer@uchealth.com
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Recruiting
      • Stephenson Cancer Center
      • Contact: Christina Caldwell; Phone Number: 48171 405-271-8001; Email: Christina-Caldwell@ouhsc.edu
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Hospital of the University of Pennsylvania
      • Contact: Jimar Hill; Phone Number: 215 349 8245; Email: Jimar.Hill@pennmedicine.upenn.edu
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • SCRI Oncology Partners
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Baylor College of Medicine
      • Contact: Henry Atencio; Phone Number: 713-798-3743; Email: Henry.VillalobosAtencio@bcm.edu
      • Contact: Glenn Wilson; Phone Number: 713-798-3468; Email: ggwilson@bcm.edu
    • Houston, Texas, United States, 77030
      • Recruiting
      • The University of Texas MD Anderson Cancer Center
      • Contact: Email: GIclinicaltrials@mdanderson.org
    • Irving, Texas, United States, 75039
      • Recruiting
      • NEXT Oncology Dallas
      • Contact: Idara Ukpong; Phone Number: 972.893.8800; Email: iukpong@nextoncology.com
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Recruiting
      • Huntsman Cancer Institute, University of Utah
      • Contact: Susan Sharry; Phone Number: (801) 585-3453; Email: (Susan.Sharry@hci.utah.edu)
  • Virginia
    • Fairfax, Virginia, United States, 22314
      • Recruiting
      • Virginia Cancer Specialists
      • Contact: Karina Castillo; Phone Number: 571.350.8758; Email: Karina.CastilloGrady@usoncology.com
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Fred Hutchinson Cancer Center
      • Contact: Matt Sherman; Phone Number: 206-606-6347; Email: mfsherman@fredhutch.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

All Patients (unless otherwise noted):

• ≥ 18 years of age
• ECOG PS is 0 to 1
• Adequate organ function as outlined by the study
• Pathologically or cytologically documented pancreatic carcinoma or poorly differentiated pancreatic carcinoma with metastatic disease or RAS-mutated, histologically or cytologically confirmed colorectal adenocarcinoma with documented unresectable or metastatic disease (Subprotocol A, B, and C)
• Presence of RAS G12D mutation (Subprotocol D, E, F)

Exclusion Criteria:

All Patients:

• Primary central nervous system (CNS) tumors
• Impaired gastrointestinal (GI) function that may significantly alter the absorption of RMC drugs
• Major surgery within 28 days of first dose

Other inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Subprotocol A: RAS-mutated unresectable or metastatic CRC or metastatic PDAC; RMC-6236 (QD) and Bevacizumab with 5-fluorouracil-based regimens	Drug: bevacizumab; IV infusion; Drug: RMC-6236; Oral tablet; Drug: mFOLFOX6 regimen; IV infusion; Drug: mFOLFIRINOX regimen; IV infusion
Experimental: Subprotocol B: RAS-mutated unresectable or metastatic CRC or metastatic PDAC; RMC-6236 (QD) and Cetuximab with or without mFOLFOX6	Drug: RMC-6236; Oral tablet; Drug: mFOLFOX6 regimen; IV infusion; Drug: cetuximab; IV infusion
Experimental: Subprotocol C: metastatic PDAC; RMC-6236 (QD) and Gemcitabine with Nab-paclitaxel	Drug: gemcitabine; IV infusion; Drug: nab-paclitaxel; IV infusion; Drug: RMC-6236; Oral tablet
Experimental: Subprotocol D: RAS G12D-mutated unresectable or metastatic CRC or metastatic PDAC; RMC-9805 (QD or BID) with or without RMC-6236 (QD), and Bevacizumab with 5-fluorouracil- based regimens	Drug: bevacizumab; IV infusion; Drug: RMC-6236; Oral tablet; Drug: mFOLFOX6 regimen; IV infusion; Drug: mFOLFIRINOX regimen; IV infusion; Drug: RMC-9805; Oral Tablet
Experimental: Subprotocol E: RAS G12D-mutated unresectable or metastatic CRC or metastatic PDAC; RMC-9805 (QD or BID) with or without RMC-6236 (QD), and Cetuximab with or without mFOLFOX6	Drug: RMC-6236; Oral tablet; Drug: mFOLFOX6 regimen; IV infusion; Drug: cetuximab; IV infusion; Drug: RMC-9805; Oral Tablet
Experimental: Subprotocol F: RAS G12D-mutated metastatic PDAC; RMC-9805 (QD or BID) with or without RMC-6236 (QD), and Gemcitabine with Nab-paclitaxel	Drug: gemcitabine; IV infusion; Drug: nab-paclitaxel; IV infusion; Drug: RMC-6236; Oral tablet; Drug: RMC-9805; Oral Tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Evaluate the safety and tolerability in the study population characterized by incidence, abnormal laboratory assessments, severity, and seriousness of adverse events in relation to the study treatment.	Up to 3 years
Dose limiting toxicities	Number of participants with dose limiting toxicities	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OS	Overall Survival	Up to 3 years
ORR	Overall Response Rate per RECIST v1.1	Up to 3 years
DOR	Duration of Response per RECIST v1.1	Up to 3 years
DCR	Incidence of Response per RECIST v1.1	Up to 3 years
TTR	Time to Response per RECIST v1.1	Up to 3 years
PFS	Progression Free Survival per RECIST v1.1	Up to 3 years
Pharmacokinetics of RMC-6236 and RMC-9805	Blood concentration of RMC-6236 and RMC-9805 over time	21 weeks

Collaborators and Investigators

• Sponsor: Revolution Medicines, Inc.
• Investigators: Study Director: Study Director, Revolution Medicines

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 24, 2024
• Primary Completion (Estimated): May 15, 2027
• Study Completion (Estimated): July 15, 2027

Study Registration Dates

• First Submitted: May 20, 2024
• First Submitted That Met QC Criteria: May 30, 2024
• First Posted (Actual): June 6, 2024

Study Record Updates

• Last Update Posted (Actual): April 1, 2026
• Last Update Submitted That Met QC Criteria: March 26, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Pancreatic Cancer; Colorectal Cancer; CRC; PDAC; RAS Wild-type; Pancreatic Ductal Carcinoma; RAS Mutation; KRAS G12X; KRAS Q61 Mutation; KRAS G12 Mutation; RAS G12D Mutation
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Intestinal Diseases; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Colonic Diseases; Carcinoma; Neoplasms, Ductal, Lobular, and Medullary; Carcinoma, Ductal; Colorectal Neoplasms; Pancreatic Neoplasms; Gastrointestinal Neoplasms; Carcinoma, Pancreatic Ductal; Amino Acids, Peptides, and Proteins; Proteins; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Bevacizumab; Cetuximab; Gemcitabine; 130-nm albumin-bound paclitaxel
• Other Study ID Numbers: RMC-GI-102

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No