A Phase 1/2, Open-label Study of VS-7375, a KRAS G12D (ON/OFF) Inhibitor, as Monotherapy and in Combination, in Patients With Advanced KRAS G12D-Mutated Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 295
- 试验地点
- 17
- 主要终点
- Part A: To characterize the safety, tolerability, and AE profile of escalating doses of VS-7375
研究概览
简要总结
This study will assess the safety and efficacy of VS-7375 alone and in combination in patients with advanced solid tumors harboring a KRAS G12D-mutation.
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
- •Individuals ≥18 years of age.
- •Agreement to sign and date an informed consent form (ICF) approved by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
- •Histologic or cytologic evidence of locally advanced unresectable or metastatic solid tumor harboring a KRAS G12D mutation.
- •Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- •Adequate organ function
- •Adequate cardiac function
- •Recovered from all AEs due to previous therapies to Grade ≤1 or baseline.
- •Agreement to use highly effective contraception
排除标准
- •Underwent major surgical procedure as defined by the Investigator, other than for diagnosis, within 4 weeks prior to Cycle 1 Day 1,
- •Receipt of chemotherapy, targeted therapy, or radiotherapy (excluding palliative radiation) within 4 weeks or 5 half-lives, whichever is shorter, or immunotherapy within 4 weeks prior to Cycle 1 Day 1
- •Treatment with any investigational drug at least 4 weeks or 5 half-lives, whichever is shorter, prior to Cycle 1 Day
- •History of treatment with direct and specific KRAS G12D inhibitors.
- •Symptomatic, untreated, or actively progressing known central nervous system (CNS) metastases.
- •Inability to swallow oral medications.
- •Evidence or history of uncontrolled, clinically significant hematological, renal, hepatic, endocrine, pulmonary, gastrointestinal, cardiovascular, psychiatric, coagulation, neurologic, dermatologic, autoimmune, or allergic disease
- •Individuals who are pregnant or breastfeeding.
研究组 & 干预措施
VS-7375 + Gemcitabine/Nab-Paclitaxel Dose Expansion
To determine the efficacy of VS-7375 in combination with gemcitabine/nab-paclitaxel at the RP2D in patients with advanced PDAC harboring a KRAS G12D mutation.
干预措施: VS-7375 (Drug)
VS-7375 + Gemcitabine/Nab-Paclitaxel Dose Expansion
To determine the efficacy of VS-7375 in combination with gemcitabine/nab-paclitaxel at the RP2D in patients with advanced PDAC harboring a KRAS G12D mutation.
干预措施: Gemcitabine + Nab-paclitaxel (Drug)
VS-7375 + Gemcitabine Dose Escalation
To determine the RP2D for VS-7375 in combination with gemcitabine in patients 75 years or older with advanced PDAC harboring a KRAS G12D mutation.
干预措施: VS-7375 (Drug)
VS-7375 Dose Escalation
To determine the recommended phase 2 dose (RP2D) for VS-7375 in patients with advanced solid tumors harboring a KRAS G12D mutation.
干预措施: VS-7375 (Drug)
Cetuximab + VS-7375 Dose Escalation
To determine the recommended phase 2 dose (RP2D) for cetuximab + VS-7375 in patients with advanced solid tumors harboring a KRAS G12D mutation.
干预措施: VS-7375 (Drug)
Cetuximab + VS-7375 Dose Escalation
To determine the recommended phase 2 dose (RP2D) for cetuximab + VS-7375 in patients with advanced solid tumors harboring a KRAS G12D mutation.
干预措施: Cetuximab (Drug)
VS-7375 Recommended Phase 2 Dose Expansion
To determine the efficacy of VS-7375 at the recommended phase 2 dose (RP2D) in patients with advanced PDAC, NSCLC, or solid tumors harboring a KRAS G12D mutation.
干预措施: VS-7375 (Drug)
Cetuximab + VS-7375 Recommended Phase 2 Dose Expansion
To determine the efficacy of cetuximab +VS-7375 at the recommended phase 2 dose (RP2D) in patients with advanced CRC harboring a KRAS G12D mutation.
干预措施: VS-7375 (Drug)
Cetuximab + VS-7375 Recommended Phase 2 Dose Expansion
To determine the efficacy of cetuximab +VS-7375 at the recommended phase 2 dose (RP2D) in patients with advanced CRC harboring a KRAS G12D mutation.
干预措施: Cetuximab (Drug)
VS-7375 + Carboplatin/Pemetrexed/Pembrolizumab Dose Escalation
To determine the recommended phase 2 dose (RP2D) for VS-7375 in combination with carboplatin/pemetrexed/pembrolizumab in patients with advanced 1L NSCLC harboring a KRAS G12D mutation.
干预措施: VS-7375 (Drug)
VS-7375 + Carboplatin/Pemetrexed/Pembrolizumab Dose Expansion
To determine the efficacy of VS-7375 in combination with carboplatin/pemetrexed/pembrolizumab at the RP2D in patients with advanced 1L NSCLC harboring a KRAS G12D mutation.
干预措施: VS-7375 (Drug)
VS-7375 + Gemcitabine/Nab-Paclitaxel Dose Escalation
To determine the recommended phase 2 dose (RP2D) for VS-7375 in combination with gemcitabine/nab-paclitaxel in patients with advanced PDAC harboring a KRAS G12D mutation.
干预措施: VS-7375 (Drug)
VS-7375 + Gemcitabine/Nab-Paclitaxel Dose Escalation
To determine the recommended phase 2 dose (RP2D) for VS-7375 in combination with gemcitabine/nab-paclitaxel in patients with advanced PDAC harboring a KRAS G12D mutation.
干预措施: Gemcitabine + Nab-paclitaxel (Drug)
VS-7375 + Gemcitabine Dose Escalation
To determine the RP2D for VS-7375 in combination with gemcitabine in patients 75 years or older with advanced PDAC harboring a KRAS G12D mutation.
干预措施: Gemcitabine (Drug)
VS-7375 + Gemcitabine Dose Expansion
The determine the efficacy of VS-7375 in combination with gemcitabine at the RP2D in patients 75 years or older with advanced PDAC harboring a KRAS G12D mutation.
干预措施: VS-7375 (Drug)
VS-7375 + Gemcitabine Dose Expansion
The determine the efficacy of VS-7375 in combination with gemcitabine at the RP2D in patients 75 years or older with advanced PDAC harboring a KRAS G12D mutation.
干预措施: Gemcitabine (Drug)
VS-7375 + Carboplatin/Pemetrexed/Pembrolizumab Dose Escalation
To determine the recommended phase 2 dose (RP2D) for VS-7375 in combination with carboplatin/pemetrexed/pembrolizumab in patients with advanced 1L NSCLC harboring a KRAS G12D mutation.
干预措施: Carboplatin + Pemetrexed + Pembrolizumab (Drug)
VS-7375 + Carboplatin/Pemetrexed/Pembrolizumab Dose Expansion
To determine the efficacy of VS-7375 in combination with carboplatin/pemetrexed/pembrolizumab at the RP2D in patients with advanced 1L NSCLC harboring a KRAS G12D mutation.
干预措施: Carboplatin + Pemetrexed + Pembrolizumab (Drug)
结局指标
主要结局
Part A: To characterize the safety, tolerability, and AE profile of escalating doses of VS-7375
时间窗: Up to 2.5 years
To characterize the safety, tolerability, and AE profile of escalating doses of VS-7375 administered on a daily oral schedule in participants with advanced solid tumors harboring a KRAS G12D mutation. Proportion/number of participants with AEs, TEAEs, TRAEs, SAEs, DLTs, and dose interruptions/reductions.
Part A: To identify the MTD or MFD
时间窗: Cycle 1 (each cycle is 21 days)
To identify the MTD or MFD using a BOIN design and recommend a dose for subsequent studies of VS-7375 on a daily oral schedule in participants with any KRAS G12D-mutated solid tumor. Proportion/number of participants with DLTs during the DLT assessment period (through C1D21).
Part B: To evaluate the preliminary anticancer activity of the optimal VS-7375 regimen
时间窗: Up to 2.5 years
To evaluate the preliminary anticancer activity of the optimal VS-7375 regimen identified from Part A in participants with advanced KRAS G12D-mutated PDAC (cohort B1), NSCLC (cohort B2), and other solid tumors (cohort B3). Confirmed ORR, PFS rate, unconfirmed PR and CR rates, DCR, DOR, and PFS per RECIST v1.1. Overall Survival
Part C: To characterize the safety, tolerability, and AE profile of VS-7375 in combination regimens.
时间窗: From enrollment to the end of treatment; an average of 9 months
To characterize the safety, tolerability, and AE profile of VS-7375 in the following combination regimens in participants with any solid tumor harboring a KRAS G12D mutation. * 2L+ therapy in combination with cetuximab in participants with any advanced or metastatic solid tumor harboring a KRAS G12D mutation * 1L therapy in combination with carboplatin, pembrolizumab, and pemetrexed in participants with previously untreated metastatic NSCLC * 2L+ therapy in combination with gemcitabine and nab-paclitaxel in participants with metastatic PDAC * 1L therapy in combination with gemcitabine in participants aged 75 years or older with previously untreated metastatic PDAC. Proportion/number of participants with AEs, TEAEs, TRAEs, SAEs, DLTs, and dose interruptions/reductions.
Part C: To identify a recommended dose for subsequent studies of combination dosed VS-7375.
时间窗: Cycle 1 (each cycle is 21 or 28 days)
To identify a recommended dose for subsequent studies of combination dosed VS-7375. Proportion/number of participants with DLTs during the DLT assessment period (through end of Cycle 1).
Part D: To determine the preliminary anticancer activity of the optimal regimen of VS-7375 as identified in Part C
时间窗: Up to 2.5 years
To determine the preliminary anticancer activity of the optimal regimen of VS-7375 as identified in Part C as: * 2L+ therapy in combination with cetuximab in participants with metastatic colorectal adenocarcinoma * 1L therapy in combination with carboplatin, pembrolizumab, and pemetrexed in participants with previously untreated metastatic NSCLC * 2L+ therapy in combination with gemcitabine and nab-paclitaxel in participants with metastatic PDAC * 1L therapy in combination with gemcitabine in participants aged 75 years or older with previously untreated metastatic PDAC. Confirmed ORR, PFS rate, unconfirmed PR and CR rates, DCR, DOR, and PFS per RECIST v1.1. Overall survival
次要结局
- Part C: Cohort C3: To evaluate the impact of VS-7375 on nab-paclitaxel PK(Up to 2.5 years)
- Part A: To characterize the PK of VS-7375 as 2L+ monotherapy administered on a daily oral schedule(Up to 2.5 years)
- Part A: To evaluate the preliminary anticancer activity of VS-73753 as 2L+ monotherapy(Up to 2.5 years)
- Parts B and D: To characterize the safety, tolerability, and AE profile of the recommended VS-7375 regimens from Part A and Part C(Up to 2.5 years)
- Parts B, C, and D: To continue to evaluate the PK of VS-7375 as monotherapy and in combination with other systemic therapies(Up to 2.5 years)