Study of RAS(ON) Inhibitors in Patients With Gastrointestinal Solid Tumors
- Conditions
- PDACCRCPancreatic Ductal AdenocarcinomaMetastatic Pancreatic Ductal AdenocarcinomaColorectal CancerGastrointestinal Cancer
- Interventions
- Drug: mFOLFOX6 regimenDrug: mFOLFIRINOX regimen
- Registration Number
- NCT06445062
- Lead Sponsor
- Revolution Medicines, Inc.
- Brief Summary
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
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 1130
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)
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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Subprotocol A: RAS-mutated unresectable or metastatic CRC or metastatic PDAC RMC-6236 RMC-6236 (QD) and Bevacizumab with 5-fluorouracil-based regimens Subprotocol B: RAS-mutated unresectable or metastatic CRC or metastatic PDAC RMC-6236 RMC-6236 (QD) and Cetuximab with or without mFOLFOX6 Subprotocol A: RAS-mutated unresectable or metastatic CRC or metastatic PDAC mFOLFOX6 regimen RMC-6236 (QD) and Bevacizumab with 5-fluorouracil-based regimens Subprotocol A: RAS-mutated unresectable or metastatic CRC or metastatic PDAC bevacizumab RMC-6236 (QD) and Bevacizumab with 5-fluorouracil-based regimens Subprotocol B: RAS-mutated unresectable or metastatic CRC or metastatic PDAC cetuximab RMC-6236 (QD) and Cetuximab with or without mFOLFOX6 Subprotocol D: RAS G12D-mutated unresectable or metastatic CRC or metastatic PDAC bevacizumab RMC-9805 (QD or BID) with or without RMC-6236 (QD), and Bevacizumab with 5-fluorouracil- based regimens Subprotocol D: RAS G12D-mutated unresectable or metastatic CRC or metastatic PDAC mFOLFIRINOX regimen RMC-9805 (QD or BID) with or without RMC-6236 (QD), and Bevacizumab with 5-fluorouracil- based regimens Subprotocol E: RAS G12D-mutated unresectable or metastatic CRC or metastatic PDAC mFOLFOX6 regimen RMC-9805 (QD or BID) with or without RMC-6236 (QD), and Cetuximab with or without mFOLFOX6 Subprotocol A: RAS-mutated unresectable or metastatic CRC or metastatic PDAC mFOLFIRINOX regimen RMC-6236 (QD) and Bevacizumab with 5-fluorouracil-based regimens Subprotocol D: RAS G12D-mutated unresectable or metastatic CRC or metastatic PDAC RMC-9805 RMC-9805 (QD or BID) with or without RMC-6236 (QD), and Bevacizumab with 5-fluorouracil- based regimens Subprotocol E: RAS G12D-mutated unresectable or metastatic CRC or metastatic PDAC cetuximab RMC-9805 (QD or BID) with or without RMC-6236 (QD), and Cetuximab with or without mFOLFOX6 Subprotocol B: RAS-mutated unresectable or metastatic CRC or metastatic PDAC mFOLFOX6 regimen RMC-6236 (QD) and Cetuximab with or without mFOLFOX6 Subprotocol C: metastatic PDAC gemcitabine RMC-6236 (QD) and Gemcitabine with Nab-paclitaxel Subprotocol C: metastatic PDAC nab-paclitaxel RMC-6236 (QD) and Gemcitabine with Nab-paclitaxel Subprotocol D: RAS G12D-mutated unresectable or metastatic CRC or metastatic PDAC mFOLFOX6 regimen RMC-9805 (QD or BID) with or without RMC-6236 (QD), and Bevacizumab with 5-fluorouracil- based regimens Subprotocol F: RAS G12D-mutated metastatic PDAC gemcitabine RMC-9805 (QD or BID) with or without RMC-6236 (QD), and Gemcitabine with Nab-paclitaxel Subprotocol F: RAS G12D-mutated metastatic PDAC RMC-9805 RMC-9805 (QD or BID) with or without RMC-6236 (QD), and Gemcitabine with Nab-paclitaxel Subprotocol F: RAS G12D-mutated metastatic PDAC nab-paclitaxel RMC-9805 (QD or BID) with or without RMC-6236 (QD), and Gemcitabine with Nab-paclitaxel Subprotocol D: RAS G12D-mutated unresectable or metastatic CRC or metastatic PDAC RMC-6236 RMC-9805 (QD or BID) with or without RMC-6236 (QD), and Bevacizumab with 5-fluorouracil- based regimens Subprotocol E: RAS G12D-mutated unresectable or metastatic CRC or metastatic PDAC RMC-6236 RMC-9805 (QD or BID) with or without RMC-6236 (QD), and Cetuximab with or without mFOLFOX6 Subprotocol F: RAS G12D-mutated metastatic PDAC RMC-6236 RMC-9805 (QD or BID) with or without RMC-6236 (QD), and Gemcitabine with Nab-paclitaxel Subprotocol C: metastatic PDAC RMC-6236 RMC-6236 (QD) and Gemcitabine with Nab-paclitaxel Subprotocol E: RAS G12D-mutated unresectable or metastatic CRC or metastatic PDAC RMC-9805 RMC-9805 (QD or BID) with or without RMC-6236 (QD), and Cetuximab with or without mFOLFOX6
- Primary Outcome Measures
Name Time Method Adverse events Up to 3 years 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.
Dose limiting toxicities 28 days Number of participants with dose limiting toxicities
- Secondary Outcome Measures
Name Time Method Pharmacokinetics of RMC-6236 and RMC-9805 21 weeks Blood concentration of RMC-6236 and RMC-9805 over time
ORR Up to 3 years Overall Response Rate per RECIST v1.1
DOR Up to 3 years Duration of Response per RECIST v1.1
DCR Up to 3 years Incidence of Response per RECIST v1.1
PFS Up to 3 years Progression Free Survival per RECIST v1.1
TTR Up to 3 years Time to Response per RECIST v1.1
OS Up to 3 years Overall Survival
Trial Locations
- Locations (22)
Mayo Clinic Hospital
🇺🇸Phoenix, Arizona, United States
HonorHealth Research Institute
🇺🇸Scottsdale, Arizona, United States
UCLA Hematology/Oncology- Santa Monica
🇺🇸Los Angeles, California, United States
University of Colorado Hospital-Anschutz Cancer Pavilion
🇺🇸Aurora, Colorado, United States
Mayo Clinic Cancer Center
🇺🇸Jacksonville, Florida, United States
Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
The Sidney Kimmel Comprehensive Cancer Center at John Hopkins
🇺🇸Baltimore, Maryland, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
SCRI Oncology Partners
🇺🇸Nashville, Tennessee, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Memorial Sloan Kettering Cancer Center Main Campus
🇺🇸New York, New York, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
University of Cincinnati Medical Center
🇺🇸Cincinnati, Ohio, United States
Hospital of the University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
Baylor College of Medicine
🇺🇸Houston, Texas, United States
The University of Texas MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
NEXT Oncology Dallas
🇺🇸Irving, Texas, United States
Huntsman Cancer Institute, University of Utah
🇺🇸Salt Lake City, Utah, United States
Virginia Cancer Specialists
🇺🇸Fairfax, Virginia, United States
Fred Hutchinson Cancer Center
🇺🇸Seattle, Washington, United States