Acquired Resistance to KRAS G12C Inhibitor, BRAF, BRAF Gene Mutation, BRAF Mutation-Related Tumors, BRAF V600E, BRAF V600 Mutation, Brain Metastases, Colorectal Cancer, Colorectal Carcinoma, Histiocytic Neoplasm, Histiocytosis, KRAS G12A, KRAS G12D, KRAS G12F, KRAS G12R, KRAS G12V, KRAS G13C, KRAS G13D, KRAS Mutation-Related Tumors, Metastatic Lung Cancer, Metastatic Lung Non-Small Cell Carcinoma, Non-small Cell Lung Cancer, NRAS Gene Mutation, NSCLC, Recurrent Histiocytic and Dendritic Cell Neoplasm, Recurrent Lung Cancer, Recurrent Lung Non-Small Cell Carcinoma, Recurrent NSCLC, Solid Carcinoma, Solid Tumor, Thyroid Cancer, Thyroid Carcinoma
Conditions
Keywords
BRAF Class I, BRAF Class II, BRAF Class III, KRAS, Intolerant histiocytic neoplasm, BDTX-4933, Phase 1, dose escalation, dose expansion, MAPK, mitogen-activated protein kinase, RAS, RAF, Upstream oncogenic alterations, RAF inhibitor, intracranial disease, CRAF, NRAS, RAF fusions
Brief summary
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.
Interventions
DRUGS241656
RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations
DRUGFOLFOX6/FOLFOX7
Used as a combination therapy and administered intravenously
DRUGFOLFIRI
Used as a combination therapy and administered intravenously
DRUGCetuximab
Used as a combination therapy and administered intravenously
DRUGPanitumumab
Used as a combination therapy and administered intravenously
DRUGGemcitabine
Used as a combination therapy and administered intravenously
DRUGNab-paclitaxel
Used as a combination therapy and administered intravenously
Sponsors
Institut de Recherches Internationales Servier
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation: Incidence of dose-limiting toxicities (DLTs) | The first 28-day cycle (Cycle 1) | A DLT is defined as any event meeting the DLT criteria occurring within the first 28-day cycle |
| Dose Escalation: Number of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Through study completion, approximately 5 years | — |
| Dose Optimization/Expansion: Objective response (OR) | Through study completion, approximately 5 years | — |
Secondary
| Measure | Time frame |
|---|---|
| Dose Escalation/Expansion: Incidence and severity of treatment-emergent adverse events (TEAEs) | Through study completion, approximately 5 years |
| Dose Escalation/Optimization/Expansion: Maximum plasma concentration (Cmax) of S241656 and its metabolite S243796 | Through study completion, approximately 5 years |
| Dose Escalation/Optimization/Expansion: Time of maximum plasma concentration (Tmax) of S241656 and its metabolite S243796 | Through study completion, approximately 5 years |
| Dose Escalation/Optimization/Expansion: Area under the plasma drug concentration-time curve (AUC) of S241656 and its metabolite S243796 | Through study completion, approximately 5 years |
| Dose Escalation/Optimization/Expansion: Half-life (t1/2) of S241656 and its metabolite S243796 | Through study completion, approximately 5 years |
| Dose Escalation: Objective response (OR) | Through study completion, approximately 5 years |
| Dose Escalation/Optimization/Expansion: Disease Control (DC) | Through study completion, approximately 5 years |
| Dose Escalation/Optimization/Expansion: Clinical Benefit (CB) | Through study completion, approximately 5 years |
| Dose Escalation/Optimization/Expansion: Duration of response (DOR) | Through study completion, approximately 5 years |
| Dose Escalation/Optimization/Expansion: Time to response (TTR) | Through study completion, approximately 5 years |
| Dose Escalation/Optimization/Expansion: Progression-free Survival (PFS) | Through study completion, approximately 5 years |
| Dose Escalation/Optimization/Expansion: Overall survival (OS) | Through study completion, approximately 5 years |
| Dose Optimization/Expansion: Number of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Through study completion, approximately 5 years |
| Dose Escalation/Optimization/Expansion: Number of Dose Interruptions | Through study completion, approximately 5 years |
| Dose Escalation/Optimization/Expansion: Number of Dose Reductions | Through study completion, approximately 5 years |
| Dose Escalation: Number of Dose Discontinuations | Through study completion, approximately 5 years |
| Dose Optimization/Expansion: Changes in allelic fraction of DNA sequence variants detected in ctDNA from baseline to on-treatment time points | Through study completion, approximately 5 years |
Countries
Australia, China, Denmark, France, Hong Kong, Italy, Japan, Spain, United Kingdom, United States
Contacts
CONTACTInstitut de Recherches Internationales Servier (I.R.I.S.), Clinical Studies Department
Outcome results
None listed