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RECRUITING

NCT05786924

PHASE1/PHASE2

Phase 1/2 Trial of S241656 in Selected RAS/MAPK Mutation- Positive Malignancies

Sponsor: Institut de Recherches Internationales Servier

View on ClinicalTrials.gov

Summary

BDTX-4933-101 is a first-in-human, open-label, Phase 1/2 dose escalation, dose optimization and expansion study designed to evaluate the safety and tolerability of S241656 as monotherapy and in combination with other anti-cancer therapies in participants with selected advanced malignancies. The study population for the Dose Escalation part of the study comprises adults with recurrent advanced/metastatic non-small cell lung cancer (NSCLC), Gastrointestinal (GI) cancers, and other solid tumors harboring KRAS, HRAS, NRAS, BRAF, and/or CRAF (Rapidly Accelerated Fibrosarcoma (RAF1)) mutations or alterations. A dose optimization part in adults with NSCLC may follow the dose escalation phase if the sponsor, in consultation with the safety review committee, decides it is necessary to further characterize the optimal dose. However, the study may also proceed directly to the expansion phase. The study population for the Dose Expansion part of the study comprises adults with advanced/metastatic NSCLC with KRAS and/or BRAF mutations, and with Pancreatic Ductal AdenoCarcinoma (PDAC), ColoRectal Cancer (CRC), and Biliary Tract Cancer (BTC) with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations and alterations. All patients will self-administer S241656 orally in 28-day cycles until disease progression, toxicity, withdrawal of consent, or termination of the study.

Official title: A Phase 1/2, Open-label Study of Oral S241656 (BDTX-4933) as Monotherapy and in Combination With Other Anti-Cancer Therapies in Patients With KRAS, BRAF and Other Selected RAS/MAPK Mutation-Positive Malignancies

Key Details

Gender

All

Age Range

18 Years - Any

Study Type

INTERVENTIONAL

Enrollment

554

Start Date

2023-04-18

Completion Date

2028-06

Last Updated

2026-09-16

Healthy Volunteers

No

Interventions

DRUG

S241656

RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations

DRUG

FOLFOX6/FOLFOX7

Used as a combination therapy and administered intravenously

DRUG

FOLFIRI

Used as a combination therapy and administered intravenously

DRUG

Cetuximab

Used as a combination therapy and administered intravenously

DRUG

Panitumumab

Used as a combination therapy and administered intravenously

DRUG

Gemcitabine

Used as a combination therapy and administered intravenously

DRUG

Nab-paclitaxel

Used as a combination therapy and administered intravenously

Key Inclusion Criteria: * Life expectancy of ≥ 12 weeks in the opinion of the investigator. * Histologically or cytologically confirmed recurrent locally advanced (unresectable) or metastatic solid tumors with documented RAS or RAF mutations or alterations. * Adequate bone marrow and organ function. * Recovered from toxicity to prior anti-cancer therapy. Part 1 Dose Escalation cohort ONLY: * Part 1A: Advanced/metastatic NSCLC with KRAS non-G12C, HRAS, NRAS, BRAF or CRAF (RAF1) mutations or alterations * Part 1B: Advanced/metastatic GI tumors (e.g., PDAC, CRC, and BTC) with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations or alterations * Part 1C: Advanced/metastatic PDAC with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations or alterations * Part 1D: Colorectal adenocarcinoma with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations or alterations * Part 1E: Other advanced/metastatic non-GI, non-NSCLC solid tumors with KRAS, HRAS, NRAS, BRAF, CRAF (RAF1) mutations or alterations Part 2 Dose Optimization and Expansion cohorts ONLY: * Part 2A: Advanced/metastatic NSCLC with KRAS non-G12C mutations and/or BRAF mutations * Part 2A1: Advanced/metastatic NSCLC with KRAS non-G12C mutations * Part 2A2: Advanced/metastatic NSCLC with BRAF mutations * Part 2A3: Advanced/metastatic NSCLC with KRAS non-G12C or BRAF mutations or alterations and active CNS metastatic disease * Part 2A4: Advanced/metastatic NSCLC with a KRAS G12C mutation * Part 2B1: Advanced/metastatic PDAC with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations or alterations * Part 2B2: Advanced/metastatic CRC with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations or alterations * Part 2B3: Advanced/metastatic BTC (adenocarcinoma) with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations or alterations Key Exclusion Criteria: * Cancer that has a known MEK1/2 mutation. * Known allergy/hypersensitivity to excipients of S241656 or to any of the registered IMPs administered in combination. * Any contra-indication, to use of any of the combination chemotherapy or anti-EGFR therapy partners administered as part of this trial. * Major surgery within 4 weeks of study entry or planned during study. * Ongoing anticancer therapy. * Ongoing radiation therapy. * Uncontrolled or active clinically relevant bacterial, fungal, or specific viral infection requiring systemic therapy. * Clinically significant cardiovascular disease. * Symptomatic spinal cord compression. * Evidence of active malignancy (other than study-specific malignancies) requiring systemic therapy within the next 2 years. * History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO. * Females who are pregnant or breastfeeding. * Actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study. * Prior use of experimental agents that target the KRAS/BRAF/MEK/ERK pathway.

Locations (49)

Banner Health- MD Anderson Cancer Center

Gilbert, Arizona, United States

The Angeles clinic - A cedars SINAI AFFILIATE

Los Angeles, California, United States

USC Norris Comprehensive Cancer Center

Los Angeles, California, United States

University of California, San Francisco (UCSF)

San Francisco, California, United States

University of Colorado - Aurora Cancer Center

Aurora, Colorado, United States

Yale University School of Medicine - Yale Cancer Center

New Haven, Connecticut, United States

Georgetown University Lombardi Cancer Center

Washington D.C., District of Columbia, United States

Sibley Memorial Hospital

Washington D.C., District of Columbia, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

South Texas Accelerated Research Therapeutics (START) Midwest

Grand Rapids, Michigan, United States

Masonic Cancer Center University of Minnesota

Minneapolis, Minnesota, United States

Washington University

St Louis, Missouri, United States

NYU Langone Medical Center - Perlmutter Cancer Center (NYU Cancer Institute)

New York, New York, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Duke University School of Medicine

Durham, North Carolina, United States

Cleveland Clinic

Cleveland, Ohio, United States

Sarah Canon Research Institute (SCRI) Oncology Partners

Nashville, Tennessee, United States

MD Anderson Cancer Center

Houston, Texas, United States

START San Antonio

San Antonio, Texas, United States

NEXT Virginia

Fairfax, Virginia, United States

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States

Peter MacCallum Cancer Centre

East Melbourne, Australia

Westmead Hospital

Westmead, Australia

Beijing Cancer Hospital

Beijing, China

Shandong Cancer Hospital (Cancer Hospital of Shandong First Medical University)

Jinan, China

Fudan University Zhongshan Hospital

Shanghai, China

The Second Affiliated Hospital of Soochow University

Suzhou, China

Center for Cancer and Organ Diseases - Rigshospitalet

Copenhagen, Denmark

Centre Georges Francois Leclerc

Dijon, France

Institut Curie

Paris, France

AP-HP Hopital Europeen Georges Pompidou

Paris, France

Centre Eugene Marquis

Rennes, France

Institut Gustave Roussy

Villejuif, France

Queen Mary Hospital

Hong Kong, Hong Kong

Prince of Wales

Shatin, Hong Kong

Istituto Europeo di Oncologia

Milan, Italy

IFO - Istituto Nazionale dei Tumori Regina Elena

Rome, Italy

Istituto Clinico Humanitas

Rozzano, Italy

Kanagawa Cancer Center

Kanagawa, Japan

Kyoto University Hospital

Kyoto, Japan

National Cancer Center Hospital

Tokyo, Japan

Hospital Universitario Vall d'Hebron

Barcelona, Spain

South Texas Accelerated Research Therapeutics (START) Madrid - Hospital Fundacion Jimenez Diaz

Madrid, Spain

South Texas Accelerated Research Therapeutics (START) Madrid - CIOCC

Madrid, Spain

Clinica Universidad de Navarra - Pamplona

Pamplona, Spain

Hospital Clinico Universitario de Valencia

Valencia, Spain

University College London Hospital

London, United Kingdom

Hammersmith Hospital

London, United Kingdom

The Christie NHS Foundation Trust

Manchester, United Kingdom