Recruiting
Phase 1
Phase 2

BDTX-4933

Sponsor:

Institut de Recherches Internationales Servier

Code:

NCT05786924

Conditions

Non-small Cell Lung Cancer

Histiocytic Neoplasm

Histiocytosis

BRAF Gene Mutation

BRAF V600E

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

S241656

FOLFOX6/FOLFOX7

FOLFIRI

Cetuximab

Panitumumab

Study Details

Brief 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.

Conditions

Non-small Cell Lung Cancer

Histiocytic Neoplasm

Histiocytosis

BRAF Gene Mutation

BRAF V600E

Study ID

NCT05786924

Start date

Apr 18, 2023

Status verified date

Jun, 2026

Completion date

Jun, 2028

Anticipated

Primary completion date

Jun, 2028

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

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.

Study Design

Enrollment

554 participants

Anticipated

Allocation

Non randomized

Intervention Model

Sequential

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Part 1A: Dose Escalation NSCLC

S241656 will be administered as a monotherapy at escalating dose levels until the biologically effective dose (BED) range is determined.

experimental: Part 1B: Dose Escalation GI Tumors

S241656 will be administered as a monotherapy at escalating dose levels until the BED range is determined.

experimental: Part 1C: Dose Escalation PDAC

S241656 will be administered in combination with gemcitabine/nab-paclitaxel at escalating dose levels until the BED range is determined.

experimental: Part 1D: Dose Escalation CRC

S241656 will be administered in combination with FOLFOX6/FOLFOX7 or FOLFIRI, and panitumumab or cetuximab at escalating dose levels until the BED range is determined.

experimental: Part 1E: Dose Escalation Other Solid Tumors

S241656 will be administered as a monotherapy at escalating dose levels until the BED range is determined.

experimental: Part 2A: Dose Optimization NSCLC

S241656 will be administered to further characterize the optimal dose.

experimental: Part 2A1: Dose Expansion NSCLC with KRAS non-G12C mutations

S241656 will be administered as a monotherapy in the BED range.

experimental: Part 2A2: Dose Expansion NSCLC with BRAF mutations

S241656 will be administered as a monotherapy in the BED range.

experimental: Part 2A3: Dose Expansion NSCLC with KRAS non-G12C or BRAF mutations/alterations

S241656 will be administered as a monotherapy in the BED range. Participants must also have active CNS metastatic disease

experimental: Part 2A4: Dose Expansion NSCLC with a KRAS G12C mutation

S241656 will be administered as a monotherapy in the BED range. Participants must have received and progressed upon G12C targeted therapy

experimental: Part 2B1: Dose Expansion PDAC

S241656 will be administered as a monotherapy in the BED range.

experimental: Part 2B2: Dose Expansion CRC

S241656 will be administered as a monotherapy in the BED range.

experimental: Part 2B3: Dose Expansion BTC

S241656 will be administered as a monotherapy in the BED range.

experimental: Part 2C1: Dose Expansion PDAC

S241656 will be administered in combination with anti-cancer therapies in the BED range. The combination therapies to be used will be determined in the future.

experimental: Part 2D1: Dose Expansion CRC

S241656 will be administered in combination with anti-cancer therapies in the BED range. The combination therapies to be used will be determined in the future.

experimental: Part 2F: Exploratory Food Effect

S241656 will be administered as a monotherapy.

Interventions

S241656

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

FOLFOX6/FOLFOX7

Used as a combination therapy and administered intravenously

FOLFIRI

Used as a combination therapy and administered intravenously

Cetuximab

Used as a combination therapy and administered intravenously

Panitumumab

Used as a combination therapy and administered intravenously

Gemcitabine

Used as a combination therapy and administered intravenously

Nab-paclitaxel

Used as a combination therapy and administered intravenously

Primary outcome measure

  • Dose Escalation: Incidence of dose-limiting toxicities (DLTs) [ Time Frame: The first 28-day cycle (Cycle 1) ]
  • Dose Escalation: Number of Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Through study completion, approximately 5 years ]
  • Dose Optimization/Expansion: Objective response (OR) [ Time Frame: Through study completion, approximately 5 years ]

Central Contacts and Locations

Central contacts

Institut de Recherches Internationales Servier (I.R.I.S.), Clinical Studies Department

+33 1 55 72 60 00scientificinformation@servier.com

Locations

Banner Health- MD Anderson Cancer Center

Recruiting

Gilbert, Arizona, United States, 85234

Contacts

Brandi Luzania

480-256-5488Brandi.Luzania@bannerhealth.com

Principal Investigator:

Jiaxin Niu, MD

The Angeles clinic - A cedars SINAI AFFILIATE

Recruiting

Los Angeles, California, United States, 90025

USC Norris Comprehensive Cancer Center

Recruiting

Los Angeles, California, United States, 90033

University of California, San Francisco (UCSF)

Recruiting

San Francisco, California, United States, 94143

Yale University School of Medicine - Yale Cancer Center

Recruiting

New Haven, Connecticut, United States, 06520-8028

Dana-Farber Cancer Institute

Recruiting

Boston, Massachusetts, United States, 02215

Contacts

Start Your Patient Journey to Cancer Care and Support

877-442-3324

South Texas Accelerated Research Therapeutics (START) Midwest

Recruiting

Grand Rapids, Michigan, United States, 49546

Contacts

Julie Burns

616-954-5559julie.burns@startmidwest.com

Jade Blakeman

616-954-5551jade.blakeman@startmidwest.com

Masonic Cancer Center University of Minnesota

Recruiting

Minneapolis, Minnesota, United States, 55455

Contacts

Amit Kulkarni, MBBS

612-624-0123kulkarni@umn.edu

Sara Crane

crane202@umn.edu

Washington University

Recruiting

St Louis, Missouri, United States, 63130

Contacts

Medical Oncology Clinical Call Center

314-747-1171MedicalOncologyClinicalCallCenter@dom.wustl.edu

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

Recruiting

New York, New York, United States, 10016

Memorial Sloan Kettering Cancer Center

Recruiting

New York, New York, United States, 10065

Contacts

646-608-3763

Duke University School of Medicine

Recruiting

Durham, North Carolina, United States, 27710

Cleveland Clinic

Recruiting

Cleveland, Ohio, United States, 44195

Sarah Canon Research Institute (SCRI) Oncology Partners

Recruiting

Nashville, Tennessee, United States, 37203

MD Anderson Cancer Center

Recruiting

Houston, Texas, United States, 77030

START San Antonio

Recruiting

San Antonio, Texas, United States, 78229

NEXT Virginia

Recruiting

Fairfax, Virginia, United States, 22031

Contacts

Blake Patterson

703-783-4505bpatterson@nextoncology.com

Fred Hutchinson Cancer Research Center

Recruiting

Seattle, Washington, United States, 98109

Contacts

Rebecca Wood

206-606-6970rwood1@seattlecca.org

More Information

Sponsor

Institut de Recherches Internationales Servier

Last update posted

Jun 17, 2026

Last verified

Jun, 2026

Keywords

  • BRAF Class I
  • BRAF Class II
  • BRAF Class III
  • KRAS
  • Intolerant histiocytic neoplasm
  • BDTX-4933
  • Phase 1
  • dose escalation
  • dose expansion
  • MAPK
  • mitogen-activated protein kinase
  • RAS
  • RAF
  • Upstream oncogenic alterations
  • RAF inhibitor
  • intracranial disease
  • CRAF
  • NRAS
  • RAF fusions

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-05. This information was provided to ClinicalTrials.gov by Institut de Recherches Internationales Servier on 2026-06-17.