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

Purpose

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
Recurrent Histiocytic and Dendritic Cell Neoplasm
Brain Metastases
Recurrent NSCLC
KRAS G13C
Acquired Resistance to KRAS G12C Inhibitor
KRAS G12A
KRAS G12F
KRAS G12R
KRAS G13D

Eligibility

Eligible Ages: Over 18 Years
Eligible Sex: All
Accepts Healthy Volunteers: No

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

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.

Study Design

Phase: Phase 1/Phase 2
Study Type: Interventional
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Primary Purpose: Treatment
Masking: None (Open Label)

Arm Groups

Arm	Description	Assigned Intervention
Experimental Part 1A: Dose Escalation NSCLC	S241656 will be administered as a monotherapy at escalating dose levels until the biologically effective dose (BED) range is determined.	Drug: S241656 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
Experimental Part 1B: Dose Escalation GI Tumors	S241656 will be administered as a monotherapy at escalating dose levels until the BED range is determined.	Drug: S241656 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
Experimental Part 1C: Dose Escalation PDAC	S241656 will be administered in combination with gemcitabine/nab-paclitaxel at escalating dose levels until the BED range is determined.	Drug: S241656 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 Drug: Gemcitabine Used as a combination therapy and administered intravenously Drug: Nab-paclitaxel Used as a combination therapy and administered intravenously
Experimental Part 1D: Dose Escalation CRC	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 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 Drug: FOLFOX6/FOLFOX7 Used as a combination therapy and administered intravenously Drug: FOLFIRI Used as a combination therapy and administered intravenously Drug: Cetuximab Used as a combination therapy and administered intravenously Drug: Panitumumab Used as a combination therapy and administered intravenously
Experimental Part 1E: Dose Escalation Other Solid Tumors	S241656 will be administered as a monotherapy at escalating dose levels until the BED range is determined.	Drug: S241656 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
Experimental Part 2A: Dose Optimization NSCLC	S241656 will be administered to further characterize the optimal dose.	Drug: S241656 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
Experimental Part 2A1: Dose Expansion NSCLC with KRAS non-G12C mutations	S241656 will be administered as a monotherapy in the BED range.	Drug: S241656 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
Experimental Part 2A2: Dose Expansion NSCLC with BRAF mutations	S241656 will be administered as a monotherapy in the BED range.	Drug: S241656 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
Experimental Part 2A3: Dose Expansion NSCLC with KRAS non-G12C or BRAF mutations/alterations	S241656 will be administered as a monotherapy in the BED range. Participants must also have active CNS metastatic disease	Drug: S241656 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
Experimental Part 2A4: Dose Expansion NSCLC with a KRAS G12C mutation	S241656 will be administered as a monotherapy in the BED range. Participants must have received and progressed upon G12C targeted therapy	Drug: S241656 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
Experimental Part 2B1: Dose Expansion PDAC	S241656 will be administered as a monotherapy in the BED range.	Drug: S241656 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
Experimental Part 2B2: Dose Expansion CRC	S241656 will be administered as a monotherapy in the BED range.	Drug: S241656 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
Experimental Part 2B3: Dose Expansion BTC	S241656 will be administered as a monotherapy in the BED range.	Drug: S241656 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
Experimental Part 2C1: Dose Expansion PDAC	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 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
Experimental Part 2D1: Dose Expansion CRC	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 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
Experimental Part 2F: Exploratory Food Effect	S241656 will be administered as a monotherapy.	Drug: S241656 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

Recruiting Locations

More Details

Status: Recruiting
Sponsor: Institut de Recherches Internationales Servier

Study Contact

Institut de Recherches Internationales Servier (I.R.I.S.), Clinical Studies Department
+33 1 55 72 60 00
scientificinformation@servier.com

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.