Non-small Cell Lung CancerPhase 1/2NCT05786924
Phase 1/2 Trial of S241656 in Selected RAS/MAPK Mutation- Positive Malignancies
A Phase 1/2 study testing S241656, FOLFOX6/FOLFOX7 and FOLFIRI in people with Non-small Cell Lung Cancer and Histiocytic Neoplasm, run by Institut de Recherches Internationales Servier at 49 sites in 10 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Non-small Cell Lung Cancer, Histiocytic Neoplasm, Histiocytosis
- What is being tested?
- S241656, FOLFOX6/FOLFOX7 and FOLFIRI
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 554 participants
- Where
- 49 sitesin 10 countries
- Study dates
- 18 Apr 2023to Jun 2028
- Phase
- Phase 1/2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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.
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- 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.
Trial locations and contacts
49 sites in 10 countries. Contact the study team or a site near you to ask about taking part.
Institut de Recherches Internationales Servier (I.R.I.S.), Clinical Studies Department contact
49 sites in 10 countries
United States21 sites, 21 recruiting
- Not yet recruiting
University of Colorado - Aurora Cancer Center
Aurora, Colorado, 80045
Halle Kuykendall, 720-848-0356, halle.kuykendall@cuanschutz.edu
- Recruiting
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
Start Your Patient Journey to Cancer Care and Support, 877-442-3324
- Recruiting
Cleveland Clinic
Cleveland, Ohio, 44195
- Recruiting
Duke University School of Medicine
Durham, North Carolina, 27710
- Recruiting
NEXT Virginia
Fairfax, Virginia, 22031
Blake Patterson, 703-783-4505, bpatterson@nextoncology.com
- Recruiting
Banner Health- MD Anderson Cancer Center
Gilbert, Arizona, 85234
Brandi Luzania, 480-256-5488, Brandi.Luzania@bannerhealth.com
Jiaxin Niu, MD
- Recruiting
South Texas Accelerated Research Therapeutics (START) Midwest
Grand Rapids, Michigan, 49546
Julie Burns, 616-954-5559, julie.burns@startmidwest.com
Jade Blakeman, 616-954-5551, jade.blakeman@startmidwest.com
- Recruiting
MD Anderson Cancer Center
Houston, Texas, 77030
- Recruiting
The Angeles clinic - A cedars SINAI AFFILIATE
Los Angeles, California, 90025
- Recruiting
USC Norris Comprehensive Cancer Center
Los Angeles, California, 90033
- Recruiting
Masonic Cancer Center University of Minnesota
Minneapolis, Minnesota, 55455
Amit Kulkarni, MBBS, 612-624-0123, kulkarni@umn.edu
Sara Crane, crane202@umn.edu
- Recruiting
Sarah Canon Research Institute (SCRI) Oncology Partners
Nashville, Tennessee, 37203
- Recruiting
Yale University School of Medicine - Yale Cancer Center
New Haven, Connecticut, 06520-8028
- Recruiting
NYU Langone Medical Center - Perlmutter Cancer Center (NYU Cancer Institute)
New York, New York, 10016
- Recruiting
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
Michael Offin, MD
646-608-3763
- Recruiting
START San Antonio
San Antonio, Texas, 78229
- Recruiting
University of California, San Francisco (UCSF)
San Francisco, California, 94143
- Recruiting
Fred Hutchinson Cancer Research Center
Seattle, Washington, 98109
Rebecca Wood, 206-606-6970, rwood1@seattlecca.org
- Recruiting
Washington University
St Louis, Missouri, 63130
Medical Oncology Clinical Call Center, 314-747-1171, MedicalOncologyClinicalCallCenter@dom.wustl.edu
- Not yet recruiting
Georgetown University Lombardi Cancer Center
Washington D.C., District of Columbia, 20007
202-444-2223, Chul.Kim@gunet.georgetown.edu
Chul Kim, MD
- Not yet recruiting
Sibley Memorial Hospital
Washington D.C., District of Columbia, 20016
France5 sites, 5 recruiting
- Not yet recruiting
Centre Georges Francois Leclerc
Dijon, 21079
- Not yet recruiting
Institut Curie
Paris, 75005
- Recruiting
AP-HP Hopital Europeen Georges Pompidou
Paris, 75015
- Recruiting
Centre Eugene Marquis
Rennes, 35042
- Not yet recruiting
Institut Gustave Roussy
Villejuif, 94805
Spain5 sites, 5 recruiting
- Not yet recruiting
Hospital Universitario Vall d'Hebron
Barcelona, 8035
- Recruiting
South Texas Accelerated Research Therapeutics (START) Madrid - Hospital Fundacion Jimenez Diaz
Madrid, 28040
- Recruiting
South Texas Accelerated Research Therapeutics (START) Madrid - CIOCC
Madrid, 28050
- Not yet recruiting
Clinica Universidad de Navarra - Pamplona
Pamplona, 31008
- Not yet recruiting
Hospital Clinico Universitario de Valencia
Valencia, 646010
China4 sites, 4 recruiting
- Recruiting
Beijing Cancer Hospital
Beijing, 100142
- Recruiting
Shandong Cancer Hospital (Cancer Hospital of Shandong First Medical University)
Jinan, 250117
- Not yet recruiting
Fudan University Zhongshan Hospital
Shanghai, 200032
- Recruiting
The Second Affiliated Hospital of Soochow University
Suzhou, 215004
Italy3 sites, 3 recruiting
- Not yet recruiting
Istituto Europeo di Oncologia
Milan, 20141
- Not yet recruiting
IFO - Istituto Nazionale dei Tumori Regina Elena
Rome, 00144
- Not yet recruiting
Istituto Clinico Humanitas
Rozzano, 20089
Japan3 sites, 3 recruiting
- Recruiting
Kanagawa Cancer Center
Kanagawa, 241-8515
- Recruiting
Kyoto University Hospital
Kyoto, 606-8507
- Recruiting
National Cancer Center Hospital
Tokyo, 104-0045
Takafumi Koyama, +81-3-3542-2511
United Kingdom3 sites, 3 recruiting
- Recruiting
University College London Hospital
London, NW1 2PG
- Recruiting
Hammersmith Hospital
London, W12 0HS
- Recruiting
The Christie NHS Foundation Trust
Manchester, M20 4BX
Australia2 sites, 2 recruiting
- Not yet recruiting
Peter MacCallum Cancer Centre
East Melbourne, 3002
- Not yet recruiting
Westmead Hospital
Westmead, NSW 2145
Hong Kong2 sites, 2 recruiting
- Recruiting
Queen Mary Hospital
Hong Kong
- Recruiting
Prince of Wales
Shatin
Denmark1 site, 1 recruiting
- Recruiting
Center for Cancer and Organ Diseases - Rigshospitalet
Copenhagen, 2100
About this 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
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
- Being tested
- S241656, FOLFOX6/FOLFOX7, FOLFIRI, Cetuximab, Panitumumab
- 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
- Medical subject headings
- Carcinoma, Non-Small-Cell Lung, Histiocytosis, Lung Neoplasms, Thyroid Neoplasms, Colorectal Neoplasms, Brain Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
S241656Drug
Also called BDTX-4933
RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations
FOLFOX6/FOLFOX7Drug
Used as a combination therapy and administered intravenously
FOLFIRIDrug
Used as a combination therapy and administered intravenously
CetuximabDrug
Used as a combination therapy and administered intravenously
PanitumumabDrug
Used as a combination therapy and administered intravenously
GemcitabineDrug
Used as a combination therapy and administered intravenously
Nab-paclitaxelDrug
Used as a combination therapy and administered intravenously
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: Drug: S241656 |
| Part 2A: Dose Optimization NSCLC | Experimental | S241656 will be administered to further characterize the optimal dose. Receives: Drug: S241656 |
| Part 2A1: Dose Expansion NSCLC with KRAS non-G12C mutations | Experimental | S241656 will be administered as a monotherapy in the BED range. Receives: Drug: S241656 |
| Part 2A2: Dose Expansion NSCLC with BRAF mutations | Experimental | S241656 will be administered as a monotherapy in the BED range. Receives: 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 Receives: 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 Receives: Drug: S241656 |
| Part 2B1: Dose Expansion PDAC | Experimental | S241656 will be administered as a monotherapy in the BED range. Receives: Drug: S241656 |
| Part 2B2: Dose Expansion CRC | Experimental | S241656 will be administered as a monotherapy in the BED range. Receives: Drug: S241656 |
| Part 2B3: Dose Expansion BTC | Experimental | S241656 will be administered as a monotherapy in the BED range. Receives: 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. Receives: 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. Receives: Drug: S241656 |
| Part 2F: Exploratory Food Effect | Experimental | S241656 will be administered as a monotherapy. Receives: Drug: S241656 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: The first 28-day cycle (Cycle 1)
Dose Escalation: Number of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Measured: Through study completion, approximately 5 years
Dose Optimization/Expansion: Objective response (OR)
Measured: Through study completion, approximately 5 years
Secondary outcomes (17)
Dose Escalation/Expansion: Incidence and severity of treatment-emergent adverse events (TEAEs)
Measured: Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Maximum plasma concentration (Cmax) of S241656 and its metabolite S243796
Measured: Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Time of maximum plasma concentration (Tmax) of S241656 and its metabolite S243796
Measured: 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
Measured: Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Half-life (t1/2) of S241656 and its metabolite S243796
Measured: Through study completion, approximately 5 years
Dose Escalation: Objective response (OR)
Measured: Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Disease Control (DC)
Measured: Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Clinical Benefit (CB)
Measured: Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Duration of response (DOR)
Measured: Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Time to response (TTR)
Measured: Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Progression-free Survival (PFS)
Measured: Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Overall survival (OS)
Measured: Through study completion, approximately 5 years
Dose Optimization/Expansion: Number of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Measured: Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Number of Dose Interruptions
Measured: Through study completion, approximately 5 years
Dose Escalation/Optimization/Expansion: Number of Dose Reductions
Measured: Through study completion, approximately 5 years
Dose Escalation: Number of Dose Discontinuations
Measured: 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
Measured: Through study completion, approximately 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Mar 2023
- Study start18 Apr 2023
- Primary completionJun 2028 (estimated)
- Study completionJun 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Non-small Cell Lung CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 554 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Institut de Recherches Internationales Servier
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05786924
- Sponsor's protocol ID
- BDTX-4933-101
- Other IDs
- 2025-523474-16-00, 2025
- Status last verified
- Oct 2026
- First submitted
- 6 Mar 2023
- Last updated
- 13 Oct 2026
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No