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

Prior treatment

• Major surgery within 4 weeks of study entry or planned during study.
• Ongoing anticancer therapy.
• Ongoing radiation therapy.
• 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.

Other illness

• 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.
• Uncontrolled or active clinically relevant bacterial, fungal, or specific viral infection requiring systemic therapy.
• Clinically significant cardiovascular disease.
• Evidence of active malignancy (other than study-specific malignancies) requiring systemic therapy within the next 2 years.

Lab values

• Any contra-indication, to use of any of the combination chemotherapy or anti-EGFR therapy partners administered as part of this trial.

Other

• Symptomatic spinal cord compression.
• History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO.
• Females who are pregnant or breastfeeding.

• 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