Dose Escalation and Dose Expansion Study of RMC-6291 Monotherapy in Subjects With Advanced KRASG12C Mutant Solid Tumors

Phase 1/1b, Multicenter, Open-Label, Dose Escalation and Dose Expansion Study of RMC-6291 Monotherapy in Subjects With Advanced KRASG12C Mutant Solid Tumors

The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics (PK) of escalating doses of RMC-6291 (KRAS G12C(ON) inhibitor) monotherapy in adult subjects with advanced solid tumors and to identify the maximum tolerated dose (MTD), and the recommended Phase 2 dose.

Study Overview

• Status: Active, not recruiting
• Conditions: Advanced Solid Tumor; Pancreatic Ductal Adenocarcinoma; Non-Small Cell Lung Cancer (NSCLC); Colorectal Cancer (CRC)
• Intervention / Treatment: Drug: RMC-6291

Detailed Description

This is an open-label, multicenter, Phase 1/1b study of RMC-6291 monotherapy in subjects with advanced KRASG12C-mutant solid tumors. The study will include 2 components: a Dose-Escalation and a Dose-Expansion. Subjects will be treated until disease progression per RECIST v1.1, unacceptable toxicity, or other criteria for withdrawal are met, whichever occurs first.

• Study Type: Interventional
• Enrollment (Estimated): 222
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2228
      • Southside Cancer Care Centre
  • Victoria
    • Frankston, Victoria, Australia, 3199
      • Peninsula & South Eastern Haematology and Oncology Group
    • Heidelberg, Victoria, Australia, 3084
      • Austin Health, Olivia Newton-John Cancer Research & Wellness Centre
    • Warrnambool, Victoria, Australia, 3280
      • South West Health Care
• Czechia
  • Hořovice, Czechia, 268 31
    • NH Hospital a.s.
  • Hradec Králové, Czechia, 50005
    • Klinika onkologie a radioterapie, Fakultni Nemocnice Hradec Kralove
  • Olomouc, Czechia, 77900
    • Onkologicka klinika, Fakultni Nemocnice Olomouc
• France
  • Angers, France, 49055
    • ICO
  • Bordeaux, France, 33000
    • CHU Bordeaux Hospital Saint-Andre
  • Clermont-Ferrand, France, 63011
    • Centre Jean Perrin
  • Lille, France, 59000
    • Centre Oscar Lambret
  • Lyon, France, 69008
    • Centre Leon Berard
  • Nantes, France, 44093
    • CHU Nantes
  • Strasbourg, France, 67200
    • ICANS
• Italy
  • Milan, Italy, 20162
    • S.C. Oncologia Falck, Dipartimento Ematologia ed Oncologia Niguarda Cancer Center
  • Milan, Italy, 20141
    • Istituto Europeo Oncologico
  • Naples, Italy, 80131
    • Istituto Nazionale Tumori Fondazione G. Pascale
  • Orbassano, Italy, 10043
    • Azienda Ospedaliero-Universitaria San Luigi Gonzaga
  • Pavia, Italy, 27100
    • Fondazione IRCCS Policlinico San matteo
  • Verona, Italy, 37134
    • Centro Ricerche Cliniche di Verona s.r.l.
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • University Malaya Medical Centre
  • Kuching, Malaysia, 93586
    • Sarawak General Hospital
• Poland
  • Lodz, Poland, 90-302
    • Instytut MSF Sp zoo
  • Poznan, Poland, 60-693
    • Med - Polonia Sp. z o. o.
  • Warsaw, Poland, 02-781
    • Narodowy Instytut Onkologii
• Serbia
  • Belgrade, Serbia, 11000
    • MSB General Hospital
  • Belgrade, Serbia, 11071
    • Clinical Hospital Center Bezanijska Kosa
  • Kamenitz, Serbia, 21204
    • Institute for pulmonary diseases Sremska Kamenica
• Singapore
  • Singapore, Singapore, 168583
    • National Cancer Centre Singapore
• South Korea
  • Seoul, South Korea, 3080
    • Seoul National University Hospital
  • Seoul, South Korea, 3722
    • Severance Hospital
  • Seoul, South Korea, 02708
    • Korea University Hospital
  • Gyeonggi-do
    • Suwon, Gyeonggi-do, South Korea, 16499
      • Ajou University Hospital
• Spain
  • Barcelona, Spain, 08908
    • ICO Hospitalet
  • Barcelona, Spain, 08023
    • NEXT Oncology IOB Hospital Quirónsalud
  • Madrid, Spain, 28040
    • Hospital Universitario Fundacion Jimenez Diaz
  • Madrid, Spain, 28027
    • Clinica Universidad de Navarra
  • Madrid, Spain, 28033
    • MD Anderson Cancer Center
  • Pamplona, Spain, 31008
    • Clinica Universidad de Navarra
  • Pozuelo de Alarcón, Spain, 28223
    • Hospital Universitario Quirónsalud
  • Seville, Spain, 41013
    • Hospital Universitario Virgen del Rocío
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet
• Taiwan
  • New Taipei City, Taiwan, 231
    • Taipei Tzu Chi Hospital
  • Tainan, Taiwan, 70457
    • National Cheng Kung University Hospital
  • Taipei, Taiwan, 10048
    • National Taiwan University Hospital
  • Yanchao District
    • Kaohsiung City, Yanchao District, Taiwan, 82445
      • E-DA hospital
• Thailand
  • Bangkok Noi, Thailand, 10700
    • Siriraj Hospital
  • Chiang Mai, Thailand, 50200
    • Chiang Mai University
  • Khon Kaen, Thailand, 40002
    • Khon Kaen University
• United States
  • Arkansas
    • Springdale, Arkansas, United States, 72762
      • Highlands Oncology Group
  • California
    • Orange, California, United States, 92868
      • UC Irvine Cancer Center
    • Sacramento, California, United States, 95817
      • UC Davis Cancer Center
    • San Francisco, California, United States, 94158
      • UCSF
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami School of Medicine Sylvester Comprehensive Cancer Center
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • American Oncology Partners of Maryland
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • New York
    • Buffalo, New York, United States, 14203
      • Roswell Park Comprehensive Cancer Center
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Center
    • New York, New York, United States, 10021
      • MSK Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology
  • Texas
    • San Antonio, Texas, United States, 78229
      • NEXT Oncology
    • San Antonio, Texas, United States, 78229
      • START
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • NEXT Oncology Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subject must be ≥18 years of age.
• Subject must have pathologically documented, locally advanced or metastatic KRASG12C-mutated solid tumor malignancy (not amenable to curative surgery) that has previously been treated with standard-of-care therapies for respective tumor types, is intolerant to, or is considered ineligible for standard-of-care anticancer treatments.
• ECOG performance status 0 or 1
• Prior treatment with a KRASG12C (OFF) inhibitor allowed for dose escalation and for NSCLC in dose expansion
• 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.
• Prior therapy with KRASG12C (ON) inhibitor

Other inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RMC-6291; Dose Escalation and Dose Expansion	Drug: RMC-6291; Oral tablet once or twice a day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Number of participants with adverse events	up to 3 years
Dose Limiting Toxicities	Number of participants with dose limiting toxicities	The first 21 days (i.e. Cycle 1)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Blood Concentration of RMC-6291	Cmax	7 Cycles
Time to Reach Maximum Blood Concentration of RMC-6291	Tmax	7 Cycles
Area Under Blood Concentration Time Curve of RMC-6291	AUC	7 Cycles
Elimination Half-Life of RMC-6291	t1/2	7 Cycles
Ratio of accumulation of RMC-6291 from a single dose to steady state with repeated dosing	accumulation ratio	7 Cycles
Overall Response Rate (ORR)	Overall response rate per RECIST v1.1	3 years
Duration of Response (DOR)	Duration of response per RECIST v1.1	3 years
Disease Control Rate (DCR)	Disease control rate per RECIST v1.1	3 years
Time to Response (TTR)	Time to response per RECIST v1.1	3 years
Progression-Free Survival (PFS)	Progression-free survival per RECIST v1.1	3 years

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Schulze CJ, Seamon KJ, Zhao Y, Yang YC, Cregg J, Kim D, Tomlinson A, Choy TJ, Wang Z, Sang B, Pourfarjam Y, Lucas J, Cuevas-Navarro A, Ayala-Santos C, Vides A, Li C, Marquez A, Zhong M, Vemulapalli V, Weller C, Gould A, Whalen DM, Salvador A, Milin A, Saldajeno-Concar M, Dinglasan N, Chen A, Evans J, Knox JE, Koltun ES, Singh M, Nichols R, Wildes D, Gill AL, Smith JAM, Lito P. Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS. Science. 2023 Aug 18;381(6659):794-799. doi: 10.1126/science.adg9652. Epub 2023 Aug 17.

Study record dates

Study Major Dates

• Study Start (Actual): September 19, 2022
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): September 30, 2027

Study Registration Dates

• First Submitted: July 11, 2022
• First Submitted That Met QC Criteria: July 13, 2022
• First Posted (Actual): July 18, 2022

Study Record Updates

• Last Update Posted (Actual): May 15, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Lung Cancer; NSCLC; Gastric Cancer; Targeted therapy; Pancreatic Cancer; Colorectal Cancer; Ovarian Cancer; KRAS mutation; STK11/LKB1; KEAP1; bronchial neoplasms; respiratory tract neoplasms; neoplasms by site; neoplasms; respiratory tract diseases; Endometrial Cancer; Rectal Cancer; Colon Cancer; Non-small Cell Lung Cancer; Thoracic Neoplasms; Esophageal cancer; Metastatic cancer; KRAS; CRC; lung disease; Ampullary cancer; PDAC; Intestinal Neoplasms; Gastrointestinal Neoplasms; Gynecological Cancer; Colonic Neoplasms; Lung Neoplasms; RMC-6291; RAS(ON); KRASG12C; KRASG12C(ON); Carcinoma, Non-Small Cell Lung; Appendiceal Cancer; Carcinoma, Pancreatic Ductal
• 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-6291-001

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