A Study of S241656 in Patients With KRAS, BRAF and Other Selected RAS/MAPK Mutation-Positive Malignancies

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut De Recherches Internationales Servier IRIS

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2026-04-21

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

ADIR

External identifiers

EU CT number

2025-523474-16-00

ClinicalTrials.gov

NCT05786924

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Pharmacodynamic, Safety, Others, Dose response

Dose Escalation: To evaluate the safety and tolerability of S241656 in the different indications and cumulatively when administered as monotherapy and in combination
Dose Expansion: To evaluate the antitumor activity of S241656 when administered as a monotherapy and in combination

Secondary objectives 6

1. 1. Dose Escalation: To characterize the plasma PK profile of S241656 and its metabolite S243796
2. 2. Dose Escalation: To evaluate the antitumor activity of S241656 when administered as monotherapy and in combinations.
3. 3. Dose Escalation: Estimate the Biologically Effective Dose range of S241656 in different indications when administered as monotherapy and in combinations.
4. 4. Dose Expansion: Evaluate and confirm the biologically effective dose of S241656 in the different indications when administered as monotherapy and in combination
5. 5. Dose Expansion: To further evaluate the antitumor activity of S241656
6. 6. Dose Expansion: To characterize the plasma PK profile of S241656 and its metabolite S243796

Conditions and MedDRA coding

Malignancies with Documented KRAS, BRAF and Other Selected RAS/MAPK Mutations

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 1. Life expectancy of ≥ 12 weeks in the opinion of the investigator
2. 2. Histologically or cytologically confirmed recurrent locally advanced (unresectable) or metastatic solid tumors with documented RAS or RAF mutations or alterations.
3. 3. Adequate bone marrow and organ function.
4. 4. Recovered from toxicity to prior anti-cancer therapy.
5. 5. 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
6. 6. 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 15

1. 1. Cancer that has a known MEK1/2 mutation.
2. 10. Evidence of active malignancy (other than study-specific malignancies) requiring systemic therapy within the next 2 years.
3. 11. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO.
4. 12. Females who are pregnant or breastfeeding.
5. 13. Actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study.
6. 14. Prior use of experimental agents that target the KRAS/BRAF/MEK/ERK pathway.
7. 2. Known allergy/hypersensitivity to excipients of S241656 or to any of the registered IMPs administered in combination.
8. 3. Any contra-indication, to use of any of the combination chemotherapy or anti-EGFR therapy partners administered as part of this trial.
9. 4. Major surgery within 4 weeks of study entry or planned during study.
10. 5. Ongoing anticancer therapy.
11. 6. Ongoing radiation therapy.
12. 7. Uncontrolled or active clinically relevant bacterial, fungal, or specific viral infection requiring systemic therapy.
13. 8. Clinically significant cardiovascular disease.
14. 9. Symptomatic spinal cord compression.
15. 15. History or current evidence of non-infectious interstitial lung disease (ILD), pneumonitis, or pulmonary fibrosis

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Dose Escalation: Incidence of dose-limiting toxicities occurring within the first 28-day cycle Number of Adverse Events and Serious Adverse Events Dose Expansion: Objective response

Secondary endpoints 6

1. 1. Dose Escalation: PK parameters of S241656 and its metabolite S243796, including but not limited to Cmax, tmax, AUC, and t½
2. 2. Dose Escalation: Objective response Disease Control Clinical Benefit Duration of Response Time to response Progression free survival Overall survival
3. 3. Dose Escalation: Clinical efficacy parameters Safety and tolerability parameters PK including: Exposure-toxicity relationship
4. 4. Dose Expansion: Clinical Efficacy Parameters Safety and Tolerability Parameters PK & PD parameters
5. 5. Dose Expansion: Disease Control Clinical Benefit Duration of Response Time to Response Progression free survival Overall Survival
6. 6. Dose Expansion: PK parameters of S241656 and its metabolite S243796, but not limited to Cmax, tmax, AUC, and t½

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 11

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut De Recherches Internationales Servier IRIS

Sponsor organisation

Institut De Recherches Internationales Servier IRIS

Address

22 Route 128

City

Gif Sur Yvette

Postcode

91190

Country

France

Scientific contact point

Organisation

Institut De Recherches Internationales Servier IRIS

Contact name

Clinical Studies Department

Public contact point

Organisation

Institut De Recherches Internationales Servier IRIS

Contact name

Clinical Studies Department

Third parties 9

Locations

4 EU/EEA countries · 14 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 39 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications