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

ConditionsNon-small Cell Lung CancerHistiocytic NeoplasmHistiocytosisBRAF Gene MutationBRAF V600EBRAF V600 MutationBRAF Mutation-Related TumorsBRAFMetastatic Lung Non-Small Cell CarcinomaMetastatic Lung CancerRecurrent Lung CancerRecurrent Lung Non-Small Cell CarcinomaNSCLCSolid TumorSolid CarcinomaKRAS G12DKRAS G12VKRAS Mutation-Related TumorsNRAS Gene MutationThyroid CancerThyroid CarcinomaColorectal CancerColorectal CarcinomaRecurrent Histiocytic and Dendritic Cell NeoplasmBrain MetastasesRecurrent NSCLCKRAS G13CAcquired Resistance to KRAS G12C InhibitorKRAS G12AKRAS G12FKRAS G12RKRAS G13D
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorInstitut de Recherches Internationales Servier

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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.

Disqualifiers

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.

Trial design

Design model

Sequential

Treatments tested in this trial

  • S241656

    Drug

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

  • 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

Treatment groups

554 Participants
are divided into 16 treatment groups

16

Treatment groups

See each treatment group below.

Group A: Part 1A: Dose Escalation NSCLCExperimental treatment 1 intervention
Group B: Part 1B: Dose Escalation GI TumorsExperimental treatment 1 intervention
Group C: Part 1C: Dose Escalation PDACExperimental treatment 3 interventions
Group D: Part 1D: Dose Escalation CRCExperimental treatment 5 interventions
Group E: Part 1E: Dose Escalation Other Solid TumorsExperimental treatment 1 intervention
Group F: Part 2A: Dose Optimization NSCLCExperimental treatment 1 intervention
Group G: Part 2A1: Dose Expansion NSCLC with KRAS non-G12C mutationsExperimental treatment 1 intervention
Group H: Part 2A2: Dose Expansion NSCLC with BRAF mutationsExperimental treatment 1 intervention
Group I: Part 2A3: Dose Expansion NSCLC with KRAS non-G12C or BRAF mutations/alterationsExperimental treatment 1 intervention
Group J: Part 2A4: Dose Expansion NSCLC with a KRAS G12C mutationExperimental treatment 1 intervention
Group K: Part 2B1: Dose Expansion PDACExperimental treatment 1 intervention
Group L: Part 2B2: Dose Expansion CRCExperimental treatment 1 intervention
Group M: Part 2B3: Dose Expansion BTCExperimental treatment 1 intervention
Group N: Part 2C1: Dose Expansion PDACExperimental treatment 1 intervention
Group O: Part 2D1: Dose Expansion CRCExperimental treatment 1 intervention
Group P: Part 2F: Exploratory Food EffectExperimental treatment 1 intervention

Trial outcomes

Primary outcomes

1

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

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

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Institut de Recherches Internationales Servier

Lead sponsor

Source ClinicalTrials.gov
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