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NCT Number: NCT05786924

Phase 1/2 Trial of S241656 in 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.

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Key information

Conditions

Non-small Cell Lung Cancer Acquired Resistance to KRAS G12C Inhibitor BRAF BRAF Gene Mutation BRAF Mutation-Related Tumors BRAF V600 Mutation BRAF V600E Brain Diseases Brain Metastases Brain Neoplasms Bronchial Neoplasms Carcinoma, Bronchogenic Carcinoma, Non-Small-Cell Lung Central Nervous System Diseases Central Nervous System Neoplasms Colonic Diseases Colorectal Cancer Colorectal Carcinoma Colorectal Neoplasms Digestive System Diseases Digestive System Neoplasms Endocrine Gland Neoplasms Endocrine System Diseases Gastrointestinal Diseases Gastrointestinal Neoplasms Head and Neck Neoplasms Hemic and Lymphatic Diseases Histiocytic Neoplasm Histiocytosis Intestinal Diseases Intestinal Neoplasms KRAS G12A KRAS G12D KRAS G12F KRAS G12R KRAS G12V KRAS G13C KRAS G13D KRAS Mutation-Related Tumors Lung Diseases Lung Neoplasms Lymphatic Diseases Metastatic Lung Cancer Metastatic Lung Non-Small Cell Carcinoma NRAS Gene Mutation NSCLC Neoplasms Neoplasms by Site Nervous System Diseases Nervous System Neoplasms Rectal Diseases Recurrent Histiocytic and Dendritic Cell Neoplasm Recurrent Lung Cancer Recurrent Lung Non-Small Cell Carcinoma Recurrent NSCLC Respiratory Tract Diseases Respiratory Tract Neoplasms Solid Carcinoma Solid Tumor Thoracic Neoplasms Thyroid Cancer Thyroid Carcinoma Thyroid Diseases Thyroid Neoplasms

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Center for Cancer and Organ Diseases - Rigshospitalet, Copenhagen, Denmark

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

S241656

Drug

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

FOLFOX6/FOLFOX7

Drug

Used as a combination therapy and administered intravenously

FOLFIRI

Drug

Used as a combination therapy and administered intravenously

Cetuximab

Drug

Used as a combination therapy and administered intravenously

Panitumumab

Drug

Used as a combination therapy and administered intravenously

Gemcitabine

Drug

Used as a combination therapy and administered intravenously

Nab-paclitaxel

Drug

Used as a combination therapy and administered intravenously

Primary outcomes

  1. Dose Escalation: Incidence of dose-limiting toxicities (DLTs)

    Time frame: The first 28-day cycle (Cycle 1)

    A DLT is defined as any event meeting the DLT criteria occurring within the first 28-day cycle

  2. Dose Escalation: Number of Adverse Events (AEs) and Serious Adverse Events (SAEs)

    Time frame: Through study completion, approximately 5 years

  3. Dose Optimization/Expansion: Objective response (OR)

    Time frame: Through study completion, approximately 5 years

Secondary outcomes

  1. Dose Escalation/Expansion: Incidence and severity of treatment-emergent adverse events (TEAEs)

    Time frame: Through study completion, approximately 5 years

  2. Dose Escalation/Optimization/Expansion: Maximum plasma concentration (Cmax) of S241656 and its metabolite S243796

    Time frame: Through study completion, approximately 5 years

  3. Dose Escalation/Optimization/Expansion: Time of maximum plasma concentration (Tmax) of S241656 and its metabolite S243796

    Time frame: Through study completion, approximately 5 years

  4. Dose Escalation/Optimization/Expansion: Area under the plasma drug concentration-time curve (AUC) of S241656 and its metabolite S243796

    Time frame: Through study completion, approximately 5 years

  5. Dose Escalation/Optimization/Expansion: Half-life (t1/2) of S241656 and its metabolite S243796

    Time frame: Through study completion, approximately 5 years

  6. Dose Escalation: Objective response (OR)

    Time frame: Through study completion, approximately 5 years

  7. Dose Escalation/Optimization/Expansion: Disease Control (DC)

    Time frame: Through study completion, approximately 5 years

  8. Dose Escalation/Optimization/Expansion: Clinical Benefit (CB)

    Time frame: Through study completion, approximately 5 years

  9. Dose Escalation/Optimization/Expansion: Duration of response (DOR)

    Time frame: Through study completion, approximately 5 years

  10. Dose Escalation/Optimization/Expansion: Time to response (TTR)

    Time frame: Through study completion, approximately 5 years

  11. Dose Escalation/Optimization/Expansion: Progression-free Survival (PFS)

    Time frame: Through study completion, approximately 5 years

  12. Dose Escalation/Optimization/Expansion: Overall survival (OS)

    Time frame: Through study completion, approximately 5 years

  13. Dose Optimization/Expansion: Number of Adverse Events (AEs) and Serious Adverse Events (SAEs)

    Time frame: Through study completion, approximately 5 years

  14. Dose Escalation/Optimization/Expansion: Number of Dose Interruptions

    Time frame: Through study completion, approximately 5 years

  15. Dose Escalation/Optimization/Expansion: Number of Dose Reductions

    Time frame: Through study completion, approximately 5 years

  16. Dose Escalation: Number of Dose Discontinuations

    Time frame: Through study completion, approximately 5 years

  17. Dose Optimization/Expansion: Changes in allelic fraction of DNA sequence variants detected in ctDNA from baseline to on-treatment time points

    Time frame: Through study completion, approximately 5 years

Study contacts

Contact information is provided by the study sponsor or research team.

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

CONTACT

[email protected]

+33 1 55 72 60 00

Sponsors and collaborators

Lead sponsor

Institut de Recherches Internationales Servier

Other

Registry information

Official study 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

Important dates

Study start
2023
Primary completion
2028
Study completion
2028
First posted
Mar 28, 2023
Registry last updated
Jun 17, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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