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

NCT05786924 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: BDTX-4933-1012025-523474-16-00
• Study Type: interventional
• Target: 554
• Locations: 2 countries
• Sites: 11

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; BRAF V600 Mutation; BRAF Mutation-Related Tumors; BRAF; Metastatic Lung Non-Small Cell Carcinoma; Metastatic Lung Cancer; Recurrent Lung Cancer; Recurrent Lung Non-Small Cell Carcinoma; NSCLC; Solid Tumor; Solid Carcinoma; KRAS G12D; KRAS G12V; KRAS Mutation-Related Tumors; NRAS Gene Mutation; Thyroid Cancer; Thyroid Carcinoma; Colorectal Cancer; Colorectal Carcinoma; Brain Metastases; Recurrent NSCLC; KRAS G13C; Acquired Resistance to KRAS G12C Inhibitor; KRAS G12A; KRAS G12F; KRAS G12R; KRAS G13D; Recurrent Histiocytic and Dendritic Cell Neoplasm

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

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (17)

• 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

Study Arms (16)

Part 1A: Dose Escalation NSCLC

EXPERIMENTAL

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

Drug: S241656

Part 1B: Dose Escalation GI Tumors

EXPERIMENTAL

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

Drug: S241656

Part 1C: Dose Escalation PDAC

EXPERIMENTAL

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

Drug: S241656; Drug: Gemcitabine; Drug: Nab-paclitaxel

Part 1D: Dose Escalation CRC

EXPERIMENTAL

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; Drug: FOLFOX6/FOLFOX7; Drug: FOLFIRI; Drug: Cetuximab; Drug: Panitumumab

Part 1E: Dose Escalation Other Solid Tumors

EXPERIMENTAL

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

Drug: S241656

Part 2A: Dose Optimization NSCLC

EXPERIMENTAL

S241656 will be administered to further characterize the optimal dose.

Drug: S241656

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

EXPERIMENTAL

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

Drug: S241656

Part 2A2: Dose Expansion NSCLC with BRAF mutations

EXPERIMENTAL

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

Drug: S241656

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

EXPERIMENTAL

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

Drug: S241656

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

EXPERIMENTAL

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

Drug: S241656

Part 2B1: Dose Expansion PDAC

EXPERIMENTAL

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

Drug: S241656

Part 2B2: Dose Expansion CRC

EXPERIMENTAL

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

Drug: S241656

Part 2B3: Dose Expansion BTC

EXPERIMENTAL

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

Drug: S241656

Part 2C1: Dose Expansion PDAC

EXPERIMENTAL

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

Part 2D1: Dose Expansion CRC

EXPERIMENTAL

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

Part 2F: Exploratory Food Effect

EXPERIMENTAL

S241656 will be administered as a monotherapy.

Drug: S241656

Interventions

S241656 DRUG

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

Also known as: BDTX-4933

Part 1A: Dose Escalation NSCLC; Part 1B: Dose Escalation GI Tumors; Part 1C: Dose Escalation PDAC; Part 1D: Dose Escalation CRC; Part 1E: Dose Escalation Other Solid Tumors; Part 2A1: Dose Expansion NSCLC with KRAS non-G12C mutations; Part 2A2: Dose Expansion NSCLC with BRAF mutations; Part 2A3: Dose Expansion NSCLC with KRAS non-G12C or BRAF mutations/alterations; Part 2A4: Dose Expansion NSCLC with a KRAS G12C mutation; Part 2A: Dose Optimization NSCLC; Part 2B1: Dose Expansion PDAC; Part 2B2: Dose Expansion CRC; Part 2B3: Dose Expansion BTC; Part 2C1: Dose Expansion PDAC; Part 2D1: Dose Expansion CRC; Part 2F: Exploratory Food Effect

FOLFOX6/FOLFOX7 DRUG

Used as a combination therapy and administered intravenously

Part 1D: Dose Escalation CRC

FOLFIRI DRUG

Used as a combination therapy and administered intravenously

Part 1D: Dose Escalation CRC

Cetuximab DRUG

Used as a combination therapy and administered intravenously

Part 1D: Dose Escalation CRC

Panitumumab DRUG

Used as a combination therapy and administered intravenously

Part 1D: Dose Escalation CRC

Gemcitabine DRUG

Used as a combination therapy and administered intravenously

Part 1C: Dose Escalation PDAC

Nab-paclitaxel DRUG

Used as a combination therapy and administered intravenously

Part 1C: Dose Escalation PDAC

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Institut de Recherches Internationales Servier: lead

Study Sites (11)

Banner Health- MD Anderson Cancer Center

Gilbert, Arizona, 85234, United States

RECRUITING

University of Colorado - Aurora Cancer Center

Aurora, Colorado, 80045, United States

NOT YET RECRUITING

Georgetown University Lombardi Cancer Center

Washington D.C., District of Columbia, 20007, United States

NOT YET RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

RECRUITING

South Texas Accelerated Research Therapeutics (START) Midwest

Grand Rapids, Michigan, 49546, United States

RECRUITING

Masonic Cancer Center University of Minnesota

Minneapolis, Minnesota, 55455, United States

RECRUITING

Washington University

St Louis, Missouri, 63130, United States

RECRUITING

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

RECRUITING

NEXT Virginia

Fairfax, Virginia, 22031, United States

RECRUITING

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109, United States

RECRUITING

National Cancer Center Hospital

Tokyo, 104-0045, Japan

ACTIVE NOT RECRUITING

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Histiocytosis; Lung Neoplasms; Thyroid Neoplasms; Colorectal Neoplasms; Brain Neoplasms

Interventions

IFL protocol; Cetuximab; Panitumumab; Gemcitabine; 130-nm albumin-bound paclitaxel

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Lymphatic Diseases; Hemic and Lymphatic Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Endocrine System Diseases; Thyroid Diseases; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Central Study Contacts

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

CONTACT

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 6, 2023
• First Posted: March 28, 2023
• Study Start: April 18, 2023
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2028
• Last Updated: April 21, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (10); JP (1)