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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; NSCLC; Solid Tumor; Metastatic Lung Cancer; Metastatic Lung Non-Small Cell Carcinoma; Non-small Cell Lung Cancer; Histiocytosis; Thyroid Carcinoma; Thyroid Cancer; Brain Metastases; Recurrent Histiocytic and Dendritic Cell Neoplasm; Colorectal Carcinoma; Solid Carcinoma; KRAS Mutation-Related Tumors; BRAF V600 Mutation; Recurrent Lung Non-Small Cell Carcinoma; BRAF V600E; KRAS G12D; KRAS G12R; Recurrent NSCLC; BRAF Gene Mutation; NRAS Gene Mutation; Histiocytic Neoplasm; KRAS G12V; Recurrent Lung Cancer; BRAF Mutation-Related Tumors; BRAF; KRAS G12A; KRAS G13D; KRAS G13C; Acquired Resistance to KRAS G12C Inhibitor; KRAS G12F
• Intervention / Treatment: Drug: S241656; Drug: Gemcitabine; Drug: Nab-paclitaxel; Drug: FOLFOX6/FOLFOX7; Drug: FOLFIRI; Drug: Cetuximab; Drug: Panitumumab

• Study Type: Interventional
• Enrollment (Estimated): 554
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Institut de Recherches Internationales Servier (I.R.I.S.), Clinical Studies Department; Phone Number: +33 1 55 72 60 00; Email: scientificinformation@servier.com

Study Locations

• Japan
  • Tokyo, Japan, 104-0045
    • Active, not recruiting
    • National Cancer Center Hospital
• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Recruiting
      • Banner Health- MD Anderson Cancer Center
      • Principal Investigator: Jiaxin Niu, MD
      • Contact: Brandi Luzania; Phone Number: 480-256-5488; Email: Brandi.Luzania@bannerhealth.com
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Not yet recruiting
      • University of Colorado - Aurora Cancer Center
      • Contact: Halle Kuykendall; Phone Number: 720-848-0356; Email: halle.kuykendall@cuanschutz.edu
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20007
      • Not yet recruiting
      • Georgetown University Lombardi Cancer Center
      • Principal Investigator: Chul Kim, MD
      • Contact: Phone Number: 202-444-2223; Email: Chul.Kim@gunet.georgetown.edu
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana-Farber Cancer Institute
      • Contact: Start Your Patient Journey to Cancer Care and Support; Phone Number: 877-442-3324
  • Michigan
    • Grand Rapids, Michigan, United States, 49546
      • Recruiting
      • South Texas Accelerated Research Therapeutics (START) Midwest
      • Contact: Julie Burns; Phone Number: 616-954-5559; Email: julie.burns@startmidwest.com
      • Contact: Jade Blakeman; Phone Number: 616-954-5551; Email: jade.blakeman@startmidwest.com
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Recruiting
      • Masonic Cancer Center University of Minnesota
      • Contact: Amit Kulkarni, MBBS; Phone Number: 612-624-0123; Email: kulkarni@umn.edu
      • Contact: Sara Crane; Email: crane202@umn.edu
  • Missouri
    • St Louis, Missouri, United States, 63130
      • Recruiting
      • Washington University
      • Contact: Medical Oncology Clinical Call Center; Phone Number: 314-747-1171; Email: MedicalOncologyClinicalCallCenter@dom.wustl.edu
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center
      • Contact: Michael Offin, MD
      • Contact: Phone Number: 646-608-3763
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • Next Virginia
      • Contact: Blake Patterson; Phone Number: 703-783-4505; Email: bpatterson@nextoncology.com
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Fred Hutchinson Cancer Research Center
      • Contact: Rebecca Wood; Phone Number: 206-606-6970; Email: rwood1@seattlecca.org

Participation Criteria

Eligibility Criteria

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

Description

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 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

16

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: S241656; RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations; Other Names: BDTX-4933
Experimental: Part 1B: Dose Escalation GI Tumors; S241656 will be administered as a monotherapy at escalating dose levels until the BED range is determined.	Drug: S241656; RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations; Other Names: BDTX-4933
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.	Drug: S241656; RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations; Other Names: BDTX-4933; Drug: Gemcitabine; Used as a combination therapy and administered intravenously; Drug: Nab-paclitaxel; Used as a combination therapy and administered intravenously
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.	Drug: S241656; RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations; Other Names: BDTX-4933; 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
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.	Drug: S241656; RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations; Other Names: BDTX-4933
Experimental: Part 2A: Dose Optimization NSCLC; S241656 will be administered to further characterize the optimal dose.	Drug: S241656; RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations; Other Names: BDTX-4933
Experimental: Part 2A1: Dose Expansion NSCLC with KRAS non-G12C mutations; S241656 will be administered as a monotherapy in the BED range.	Drug: S241656; RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations; Other Names: BDTX-4933
Experimental: Part 2A2: Dose Expansion NSCLC with BRAF mutations; S241656 will be administered as a monotherapy in the BED range.	Drug: S241656; RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations; Other Names: BDTX-4933
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	Drug: S241656; RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations; Other Names: BDTX-4933
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	Drug: S241656; RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations; Other Names: BDTX-4933
Experimental: Part 2B1: Dose Expansion PDAC; S241656 will be administered as a monotherapy in the BED range.	Drug: S241656; RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations; Other Names: BDTX-4933
Experimental: Part 2B2: Dose Expansion CRC; S241656 will be administered as a monotherapy in the BED range.	Drug: S241656; RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations; Other Names: BDTX-4933
Experimental: Part 2B3: Dose Expansion BTC; S241656 will be administered as a monotherapy in the BED range.	Drug: S241656; RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations; Other Names: BDTX-4933
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.	Drug: S241656; RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations; Other Names: BDTX-4933
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.	Drug: S241656; RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations; Other Names: BDTX-4933
Experimental: Part 2F: Exploratory Food Effect; S241656 will be administered as a monotherapy.	Drug: S241656; RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations; Other Names: BDTX-4933

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Escalation: Incidence of dose-limiting toxicities (DLTs)	A DLT is defined as any event meeting the DLT criteria occurring within the first 28-day cycle	The first 28-day cycle (Cycle 1)
Dose Escalation: Number of Adverse Events (AEs) and Serious Adverse Events (SAEs)		Through study completion, approximately 5 years
Dose Optimization/Expansion: Objective response (OR)		Through study completion, approximately 5 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Dose Escalation/Expansion: Incidence and severity of treatment-emergent adverse events (TEAEs)	Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Maximum plasma concentration (Cmax) of S241656 and its metabolite S243796	Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Time of maximum plasma concentration (Tmax) of S241656 and its metabolite S243796	Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Area under the plasma drug concentration-time curve (AUC) of S241656 and its metabolite S243796	Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Half-life (t1/2) of S241656 and its metabolite S243796	Through study completion, approximately 5 years
Dose Escalation: Objective response (OR)	Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Disease Control (DC)	Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Clinical Benefit (CB)	Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Duration of response (DOR)	Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Time to response (TTR)	Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Progression-free Survival (PFS)	Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Overall survival (OS)	Through study completion, approximately 5 years
Dose Optimization/Expansion: Number of Adverse Events (AEs) and Serious Adverse Events (SAEs)	Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Number of Dose Interruptions	Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Number of Dose Reductions	Through study completion, approximately 5 years
Dose Escalation: Number of Dose Discontinuations	Through study completion, approximately 5 years
Dose Optimization/Expansion: Changes in allelic fraction of DNA sequence variants detected in ctDNA from baseline to on-treatment time points	Through study completion, approximately 5 years

Collaborators and Investigators

• Sponsor: Institut de Recherches Internationales Servier

Study record dates

Study Major Dates

• Study Start (Actual): April 18, 2023
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: March 6, 2023
• First Submitted That Met QC Criteria: March 15, 2023
• First Posted (Actual): March 28, 2023

Study Record Updates

• Last Update Posted (Actual): April 21, 2026
• Last Update Submitted That Met QC Criteria: April 16, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Phase 1; MAPK; KRAS; dose escalation; NRAS; dose expansion; RAS; RAF; BRAF Class II; BRAF Class III; BRAF Class I; Intolerant histiocytic neoplasm; BDTX-4933; mitogen-activated protein kinase; Upstream oncogenic alterations; RAF inhibitor; intracranial disease; CRAF; RAF fusions
• Additional Relevant MeSH Terms: Endocrine System Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms; Intestinal Diseases; Respiratory Tract Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Lung Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Colonic Diseases; Lymphatic Diseases; Nervous System Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Central Nervous System Neoplasms; Thyroid Diseases; Hemic and Lymphatic Diseases; Lung Neoplasms; Colorectal Neoplasms; Carcinoma, Non-Small-Cell Lung; Brain Neoplasms; Histiocytosis; Thyroid Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Panitumumab; Cetuximab; Gemcitabine; 130-nm albumin-bound paclitaxel; IFL protocol
• Other Study ID Numbers: BDTX-4933-101; 2025-523474-16-00 (Ctis)

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