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

Servier

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Colorectal Carcinoma; KRAS G12V; Solid Tumor; BRAF V600 Mutation; Brain Metastases; KRAS Mutation-Related Tumors; BRAF; KRAS G12F; Acquired Resistance to KRAS G12C Inhibitor; Recurrent Lung Cancer; KRAS G12A; Metastatic Lung Non-Small Cell Carcinoma; Non-small Cell Lung Cancer; Thyroid Cancer; NRAS Gene Mutation; Histiocytosis; BRAF Gene Mutation; KRAS G12D; BRAF V600E; NSCLC; Recurrent Histiocytic and Dendritic Cell Neoplasm; Thyroid Carcinoma; BRAF Mutation-Related Tumors; KRAS G13C; Metastatic Lung Cancer; Recurrent NSCLC; Solid Carcinoma; Histiocytic Neoplasm; KRAS G13D; KRAS G12R; Recurrent Lung Non-Small Cell Carcinoma; Colorectal Cancer

Treatments: Drug: FOLFIRI; Drug: Cetuximab; Drug: S241656; Drug: Panitumumab; Drug: Nab-paclitaxel; Drug: FOLFOX6/FOLFOX7; Drug: Gemcitabine

Study type: Interventional

Funder types: Other

Identifiers

NCT05786924

2025-523474-16-00 (EU Trial (CTIS) Number)

BDTX-4933-101

Details and patient eligibility

About

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.

Enrollment: 554 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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554 participants in 16 patient groups

Part 1A: Dose Escalation NSCLC

Experimental group

Description:

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

Treatment:

Drug: S241656

Part 1B: Dose Escalation GI Tumors

Experimental group

Description:

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

Treatment:

Drug: S241656

Part 1C: Dose Escalation PDAC

Experimental group

Description:

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

Treatment:

Drug: Gemcitabine

Drug: Nab-paclitaxel

Drug: S241656

Part 1D: Dose Escalation CRC

Experimental group

Description:

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.

Treatment:

Drug: FOLFOX6/FOLFOX7

Drug: Panitumumab

Drug: S241656

Drug: Cetuximab

Drug: FOLFIRI

Part 1E: Dose Escalation Other Solid Tumors

Experimental group

Description:

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

Treatment:

Drug: S241656

Part 2A: Dose Optimization NSCLC

Experimental group

Description:

S241656 will be administered to further characterize the optimal dose.

Treatment:

Drug: S241656

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

Experimental group

Description:

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

Treatment:

Drug: S241656

Part 2A2: Dose Expansion NSCLC with BRAF mutations

Experimental group

Description:

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

Treatment:

Drug: S241656

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

Experimental group

Description:

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

Treatment:

Drug: S241656

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

Experimental group

Description:

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

Treatment:

Drug: S241656

Part 2B1: Dose Expansion PDAC

Experimental group

Description:

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

Treatment:

Drug: S241656

Part 2B2: Dose Expansion CRC

Experimental group

Description:

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

Treatment:

Drug: S241656

Part 2B3: Dose Expansion BTC

Experimental group

Description:

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

Treatment:

Drug: S241656

Part 2C1: Dose Expansion PDAC

Experimental group

Description:

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.

Treatment:

Drug: S241656

Part 2D1: Dose Expansion CRC

Experimental group

Description:

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.

Treatment:

Drug: S241656

Part 2F: Exploratory Food Effect

Experimental group

Description:

S241656 will be administered as a monotherapy.

Treatment:

Drug: S241656