A Phase 1/2, Open-label Study of Oral S241656 (BDTX-4933) as Monotherapy and in Combination With Other Anti-Cancer Therapies in Patients With KRAS, BRAF and Other Selected RAS/MAPK Mutation-Positive Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 554
- 试验地点
- 59
- 主要终点
- Dose Optimization/Expansion: Objective response (OR)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: S241656 (Drug)
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.
干预措施: S241656 (Drug)
Part 1B: Dose Escalation GI Tumors
S241656 will be administered as a monotherapy at escalating dose levels until the BED range is determined.
干预措施: S241656 (Drug)
Part 2F: Exploratory Food Effect
S241656 will be administered as a monotherapy.
干预措施: S241656 (Drug)
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.
干预措施: Gemcitabine (Drug)
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.
干预措施: Nab-paclitaxel (Drug)
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.
干预措施: Cetuximab (Drug)
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.
干预措施: Panitumumab (Drug)
Part 1E: Dose Escalation Other Solid Tumors
S241656 will be administered as a monotherapy at escalating dose levels until the BED range is determined.
干预措施: S241656 (Drug)
Part 2A: Dose Optimization NSCLC
S241656 will be administered to further characterize the optimal dose.
干预措施: S241656 (Drug)
Part 2A1: Dose Expansion NSCLC with KRAS non-G12C mutations
S241656 will be administered as a monotherapy in the BED range.
干预措施: S241656 (Drug)
Part 2A2: Dose Expansion NSCLC with BRAF mutations
S241656 will be administered as a monotherapy in the BED range.
干预措施: S241656 (Drug)
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
干预措施: S241656 (Drug)
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
干预措施: S241656 (Drug)
Part 2B1: Dose Expansion PDAC
S241656 will be administered as a monotherapy in the BED range.
干预措施: S241656 (Drug)
Part 2B2: Dose Expansion CRC
S241656 will be administered as a monotherapy in the BED range.
干预措施: S241656 (Drug)
Part 2B3: Dose Expansion BTC
S241656 will be administered as a monotherapy in the BED range.
干预措施: S241656 (Drug)
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.
干预措施: S241656 (Drug)
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.
干预措施: FOLFIRI (Drug)
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.
干预措施: S241656 (Drug)
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.
干预措施: S241656 (Drug)
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.
干预措施: FOLFOX6/FOLFOX7 (Drug)
结局指标
主要结局
Dose Optimization/Expansion: Objective response (OR)
时间窗: Through study completion, approximately 5 years
Dose Escalation: Incidence of dose-limiting toxicities (DLTs)
时间窗: 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)
时间窗: Through study completion, approximately 5 years
次要结局
- Dose Escalation/Expansion: Incidence and severity of treatment-emergent adverse events (TEAEs)(Through study completion, approximately 5 years)
- Dose Escalation/Optimization/Expansion: Progression-free Survival (PFS)(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: 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)