Study of Elironrasib and Daraxonrasib as Monotherapies and Combination Therapy in Participants With Advanced KRAS G12C Mutant Solid Tumors

Phase 1b/2, Multicenter, Open-label, Dose Escalation and Dose Expansion Study of Elironrasib and Daraxonrasib as Monotherapies and Combination Therapy in Patients With Advanced KRAS G12C-Mutated Solid Tumors

This study is to evaluate the safety, tolerability, and PK profiles of Elironrasib and Daraxonrasib as monotherapies and combination therapy in patients with KRAS G12C-mutated solid tumors.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; Pancreatic Ductal Adenocarcinoma; Non-Small Cell Lung Cancer (NSCLC)
• Intervention / Treatment: Drug: Daraxonrasib; Drug: Elironrasib

Detailed Description

This is an open-label, multicenter, Phase 1b/2 study evaluating elironrasib and daraxonrasib, administered as monotherapy and in combination, in patients with advanced KRAS G12C-mutated solid tumors to determine the maximum tolerated dose (MTD), identify the recommended Phase 2 dose and schedule (RP2DS), and preliminarily assess antitumor activity.

The study includes a Phase 1b dose escalation and expansion of combination therapy, followed by a Phase 2 evaluation of the selected RP2DS as monotherapy and combination therapy to further assess safety and antitumor activity.

• Study Type: Interventional
• Enrollment (Estimated): 534
• Phase: Phase 2; Phase 1

Contacts and Locations

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

Study Locations

• France
  • Angers, France, 49055
    • Recruiting
    • West Cancer Institute
  • Bordeaux, France, 33000
    • Recruiting
    • Institut Bergonie
  • Bron, France, 69500
    • Recruiting
    • Hospital Louise Pradel
  • Lille, France, 59000
    • Recruiting
    • Oscar Lambret Center of Lillle
  • Lyon, France, 69373
    • Recruiting
    • Centre Leon Berard
  • Montpellier, France, 34298
    • Recruiting
    • Cancer Institute of Montpellier
  • Nantes, France, 44093
    • Recruiting
    • CHU Nantes
  • Strasbourg, France, 67033
    • Withdrawn
    • Institute of Cancer of Strasbourg
• Germany
  • Cologne, Germany, 80937
    • Recruiting
    • Universitäts Klinikum Köln
  • Esslingen am Neckar, Germany, 73730
    • Recruiting
    • Klinikum Esslingen GmbH
  • Moers, Germany, 47441
    • Recruiting
    • Krankenhaus Bethanien Moers
  • Nuremberg, Germany, 90419
    • Recruiting
    • Klinkum Nurnberg Paracelsus Medical Unviersity
• Italy
  • Ancona, Italy, 60126
    • Recruiting
    • Department of Medical Oncology - Azienda Ospedaliero Uniersitaria delle Marche
  • Aviano, Italy, 33081
    • Recruiting
    • Centro Di Riferimento Oncologico
  • Meldola, Italy, 47014
    • Recruiting
    • Institute Romagnolo per lo Studio Tumori
  • Milan, Italy, 20162
    • Recruiting
    • Niguarda Cancer Center
  • Naples, Italy, 80131
    • Recruiting
    • Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale"
  • Orbassano, Italy, 10043
    • Recruiting
    • San Luigi Hospital
  • Ravenna, Italy, 48121
    • Recruiting
    • AUSL Romagna - S.M. delle Croci Hospital
• Netherlands
  • Amsterdam, Netherlands, 1066CX
    • Recruiting
    • Netherlands Cancer Institute Antoni van Leeuwenhoek
• Puerto Rico
  • San Juan, Puerto Rico, 00935
    • Recruiting
    • Pan American Center for Oncology Trials
• Spain
  • Barcelona, Spain, 08023
    • Recruiting
    • START Barcelona - Hospital HM Nou Delfos
  • Barcelona, Spain, 08908
    • Recruiting
    • Institut Catala d'Oncologia Hospital
  • Madrid, Spain, 28041
    • Recruiting
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28027
    • Recruiting
    • University Clinic of Navarra
  • Madrid, Spain, 28033
    • Recruiting
    • Fundacion MD Anderson Cancer Center
  • Madrid, Spain, 28223
    • Recruiting
    • NEXT Oncology - Quirónsalud Madrid University Hospital
  • Madrid, Spain, 28040
    • Recruiting
    • START Madrid
  • Pamplona, Spain, 31008
    • Recruiting
    • University Clinic of Navarra
  • Seville, Spain, 41009
    • Recruiting
    • Hospital Universitario Virgen Macarena
  • Valencia, Spain, 46026
    • Recruiting
    • La Fe University and Polytechnic Hospital
  • Zaragoza, Spain, 50009
    • Recruiting
    • Hospital Universitario Miguel Servet
• United States
  • California
    • Duarte, California, United States, 91010
      • Withdrawn
      • City of Hope
    • Orange, California, United States, 92868
      • Recruiting
      • UC Irvine Health
    • Sacramento, California, United States, 95817
      • Recruiting
      • UC Davis Comprehensive Cancer Center
    • Stanford, California, United States, 94305
      • Recruiting
      • Stanford Cancer Institute
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado Cancer Center
  • Florida
    • Sarasota, Florida, United States, 34232
      • Recruiting
      • Florida Cancer Specialists
    • Tampa, Florida, United States, 33612
      • Recruiting
      • Moffitt Cancer Center and Research Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana Farber Cancer Institute
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Withdrawn
      • Henry Ford Cancer
    • Grand Rapids, Michigan, United States, 49546
      • Recruiting
      • START Midwest
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University
    • New York, New York, United States, 10032
      • Recruiting
      • NYU Langone Health
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Recruiting
      • University of Oklahoma
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • Sarah Cannon Research Institue
  • Texas
    • Dallas, Texas, United States, 75230
      • Completed
      • Mary Crowley Cancer Research
    • Houston, Texas, United States, 77030
      • Recruiting
      • MD Anderson
    • Irving, Texas, United States, 75039
      • Recruiting
      • Next Dallas
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • Next Oncology San Antonio
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • START Texas
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • NEXT Oncology Virginia

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• 18 years of age

• Histology: pathologically documented, KRAS G12C-mutated, advanced or metastatic solid tumors not amendable to curative therapy

  1. Phase 1b Dose Escalation: solid tumors, previously treated
  2. Phase 1b Dose Expansion and Phase 2:

  i. NSCLC, previously treated with immunotherapy, chemotherapy, and KRAS G12C (OFF) inhibitors ii. Solid tumors, previously treated, naïve to KRAS G12C (OFF) inhibitors.

• ECOG performance status 0 or 1
• Adequate organ function

Exclusion Criteria:

• Primary central nervous system (CNS) tumors
• Active brain metastases
• Known impairment of GI function that would alter the absorption
• Major surgical procedures within 28 days or non-study related minor procedures within 7 days of treatment

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Elironrasib Monotherapy; Phase 2 only	Drug: Elironrasib; oral tablets; Other Names: RMC-6291
Experimental: Daraxonrasib Monotherapy; Phase 2 only	Drug: Daraxonrasib; oral tablets; Other Names: RMC-6236
Experimental: Daraxonrasib + Elironrasib Combination; Phase 1b and 2	Drug: Daraxonrasib; oral tablets; Other Names: RMC-6236; Drug: Elironrasib; oral tablets; Other Names: RMC-6291

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with adverse events (AEs) in Phase 1b	Incidence and severity of treatment-emergent AEs and serious AEs as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5	Up to approximately 3 years
Changes in vital signs in Phase 1b	Number of patients with clinically significant changes in vital signs	Up to approximately 3 years
Changes in clinical laboratory test values in Phase 1b	Number of patients with clinically significant changes in clinical laboratory test values	Up to approximately 3 years
Dose Limiting Toxicities in Phase 1b	Number of participants with dose limiting toxicities	21 days
Changes in ECGs in Phase 1b	Number of patients with clinically significant changes in ECGs	Up to approximately 3 years
Overall Response Rate (ORR) in Phase 2	Overall response rate per RECIST v1.1 as assessed by blinded independent central review (BICR)	Up to approximately 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Blood Concentration of Elironrasib and Daraxonrasib	Cmax	up to 21 weeks
Time to Reach Maximum Blood Concentration of Elironrasib and Daraxonrasib	Tmax	up to 21 weeks
Area Under Blood Concentration Time Curve of Elironrasib and Daraxonrasib	AUC	up to 21 weeks
Elimination Half-Life of Elironrasib and Daraxonrasib	t1/2	up to 21 weeks
Ratio of accumulation of Elironrasib and Daraxonrasib from a single dose to steady state with repeated dosing	accumulation ratio	up to 21 weeks
Overall Response Rate (ORR) in Phase 1b	Overall response rate per RECIST v1.1	Up to approximately 3 years
Duration of Response (DOR)	Duration of response per RECIST v1.1	Up to approximately 3 years
Disease Control Rate in Phase 1b	Disease Control rate per RECIST v1.1	Up to approximately 3 years
Time to Response (TTR) in Phase 1b	Time to response per RECIST v1.1	Up to approximately 3 years
Progression-Free Survival (PFS)	Progression-free survival per RECIST v1.1	Up to approximately 3 years
Number of patients with AEs in Phase 2	Incidence and severity of treatment-emergent AEs and serious AEs as assessed by CTCAE v5	Up to approximately 3 years
Changes in vital signs in Phase 2	Number of patients with clinically significant changes in vital signs	Up to approximately 3 years
Changes in clinical laboratory values in Phase 2	Number of patients with clinically significant changes in clinical laboratory test values	Up to approximately 3 years
Overall Survival (OS) in Phase 2	OS is defined as time from enrollment until death from any cause	Up to approximately 3 years

Collaborators and Investigators

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

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): November 14, 2023
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: November 7, 2023
• First Submitted That Met QC Criteria: November 7, 2023
• First Posted (Actual): November 13, 2023

Study Record Updates

• Last Update Posted (Actual): April 23, 2026
• Last Update Submitted That Met QC Criteria: April 20, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Lung Cancer; NSCLC; Neoplasms; Gastric Cancer; Targeted therapy; Pancreatic Cancer; Colorectal Cancer; Ovarian Cancer; KRAS mutation; STK11/LKB1; KEAP1; Endometrial Cancer; Metastatic Cancer; Esophageal Cancer; Rectal Cancer; Colon Cancer; Non-small Cell Lung Cancer; Thoracic Neoplasms; KRAS; CRC; PDAC; Ampullary Cancer; Intestinal Neoplasms; Gastrointestinal Neoplasms; Gynecological Cancer; Colonic Neoplasms; Lung Neoplasms; Lung disease; RMC-6291; KRASG12C; Carcinoma, Non-Small Cell Lung; Appendiceal Cancer; Carcinoma, Pancreatic Ductal; Neoplasms by site; Respiratory tract diseases; Bronchial neoplasms; RAS (ON); KRASG12C (ON); Respiratory tract neoplasms; RMC-6236; Elironrasib; Daraxonrasib
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Pathologic Processes; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Intestinal Diseases; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Rectal Diseases; Uterine Diseases; Genital Diseases, Female; Bronchial Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Pancreatic Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Colonic Diseases; Neoplastic Processes; Esophageal Diseases; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Gonadal Disorders; Carcinoma; Carcinoma, Bronchogenic; Uterine Neoplasms; Neoplasms, Ductal, Lobular, and Medullary; Cecal Neoplasms; Cecal Diseases; Carcinoma, Ductal; Pathological Conditions, Signs and Symptoms; Neoplasms; Stomach Neoplasms; Rectal Neoplasms; Lung Diseases; Lung Neoplasms; Colorectal Neoplasms; Colonic Neoplasms; Esophageal Neoplasms; Ovarian Neoplasms; Neoplasm Metastasis; Pancreatic Neoplasms; Gastrointestinal Neoplasms; Carcinoma, Non-Small-Cell Lung; Intestinal Neoplasms; Endometrial Neoplasms; Respiratory Tract Diseases; Thoracic Neoplasms; Respiratory Tract Neoplasms; Neoplasms by Site; Appendiceal Neoplasms; Carcinoma, Pancreatic Ductal; Bronchial Neoplasms
• Other Study ID Numbers: RMC-6291-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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