A Phase 1, Open-label, Multicenter Study to Assess Safety, Tolerability, PK, and Efficacy of MK-1084 as Monotherapy and as Part of Various Combination Therapies in Participants With KRAS G12C Mutant Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 830
- 试验地点
- 124
- 主要终点
- Number of Participants Who Discontinue Study Treatment Due to an AE
研究概览
简要总结
This is a study evaluating the safety, pharmacokinetics, and efficacy of calderasib alone, and calderasib plus other combination therapies in participants with advanced solid tumors with identified kirsten rat sarcoma viral oncogene homolog G12C (KRAS G12C) mutation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •For all participants:
- •Has measurable disease by RECIST 1.1 criteria
- •Has adequate organ function
- •Male participants agree to protocol-specified contraception requirements including refraining from donating sperm and using protocol-specified contraceptives unless confirmed to be azoospermic
- •Female participants must not be pregnant or breastfeeding, and must agree to protocol-specified contraceptive requirements and must have a negative highly sensitive pregnancy test within 24 hours (for a urine test) or 72 hours (for a serum test) before the first dose of study intervention
- •For Arm 1 - Has locally advanced unresectable or metastatic solid-tumor malignancy with histologically OR blood-based confirmation of KRAS G12C mutation who has received at least 1 line of therapy for systemic disease
- •- Has an untreated metastatic non-small cell lung cancer (NSCLC) with histologically OR blood-based confirmation of KRAS G12C mutation and histologic confirmation of programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) ≥1%
- •Has locally advanced unresectable or metastatic solid-tumor malignancy with histological or blood-based confirmation of KRAS G12C mutation who has received at least 1 line of therapy for systemic disease Expansion Group A: 2L+NSCLC
- •Has histologically or cytologically confirmed diagnosis of unresectable or metastatic NSCLC with histological or blood-based confirmation of KRAS G12C mutation and submits archival tumor sample
- •Previous treatment failure of at least 1 line of systemic therapy Expansion Group B
- •Has locally advanced unresectable or metastatic solid-tumor malignancy, excluding NSCLC or CRC, with histologically or blood- based confirmation of KRAS G12C mutation who has received at least 1 line of therapy for systemic disease
- •Arm 4 only - Has an untreated advanced or metastatic nonsquamous NSCLC with histologically or blood-based confirmation of KRAS G12C mutation
- •Histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic colorectal adenocarcinoma and with histologically or blood-based confirmation of KRAS G12C mutation
- •Previous treatment failure of one or 2 previous line(s) of systemic therapy
- •- Locally advanced unresectable or metastatic colorectal adenocarcinoma with histologically or blood-based confirmation of KRAS G12C mutation
排除标准
- •Has received chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (2 weeks for palliative radiation) before first dose of study intervention
- •Has a history of second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 5 years
- •Has clinically active central nervous system (CNS) metastases and/or carcinomatous meningitis
- •Has an active infection requiring systemic therapy
- •Known history of HIV infection or. has a known history of Hepatitis B virus or known active Hepatitis C virus infection
- •Has a history of interstitial lung disease, noninfectious pneumonitis requiring active steroid therapy, or ongoing pneumonitis
- •Has an active autoimmune disease requiring systemic therapy
- •Has not fully recovered from any effects of major surgical procedure without significant detectable infection
- •Has one or more of the following ophthalmological findings/conditions: intraocular pressure >21 mm Hg and/or any diagnosis of glaucoma; diagnosis of central serous retinopathy, retinal vein occlusion, or retinal artery occlusion and/or a diagnosis of retinal degenerative disease excluding age-related macular degeneration
- •Has received live or live-attenuated vaccine within 4 weeks of study start
- •Is unable to interrupt aspirin or other nonsteroidal anti-inflammatories (NSAIDs), other than an aspirin dose ≤1.3 grams per day, for at least 2 days (5 days for long-acting agents [for example, piroxicam]) before, during, and for at least 2 days after administration of pemetrexed.
- •Is unable/unwilling to take folic acid, vitamin B12, and dexamethasone
研究组 & 干预措施
Arm 4
Participants will receive calderasib daily oral dose plus an intravenous infusion of pembrolizumab (200 mg) once every 21-day cycle for up to 35 cycles (up to ~24 months). Participants will also receive carboplatin (per label) and pemetrexed (per label) once every 21-day cycle for the first 4 cycles.
干预措施: Calderasib (Drug)
Arm 4
Participants will receive calderasib daily oral dose plus an intravenous infusion of pembrolizumab (200 mg) once every 21-day cycle for up to 35 cycles (up to ~24 months). Participants will also receive carboplatin (per label) and pemetrexed (per label) once every 21-day cycle for the first 4 cycles.
干预措施: Pembrolizumab (Biological)
Arm 5
Participants will receive calderasib daily oral dose plus an intravenous infusion of cetuximab (per label) every 2 weeks of each 28-day cycle.
干预措施: cetuximab (Biological)
Arm 1
Participants will receive daily oral escalating doses of up to 800 mg of calderasib until progressive disease or discontinuation. Dosing regimen may be adjusted based on safety.
干预措施: Calderasib (Drug)
Arm 2
Participants will receive calderasib daily oral escalating dose of up to 800 mg plus pembrolizumab given as a 200 mg intravenous infusion once every 21-day cycle up to a total of 35 cycles (up to ~24 months). Treatment with calderasib will continue until progressive disease or discontinuation. Dosing regimen may be adjusted based on safety.
干预措施: Pembrolizumab (Biological)
Arm 4
Participants will receive calderasib daily oral dose plus an intravenous infusion of pembrolizumab (200 mg) once every 21-day cycle for up to 35 cycles (up to ~24 months). Participants will also receive carboplatin (per label) and pemetrexed (per label) once every 21-day cycle for the first 4 cycles.
干预措施: carboplatin (Drug)
Arm 6
Participants will receive calderasib daily oral dose. Additionally, participants receive an intravenous infusion of cetuximab (per label) every 2 weeks of each 28-day cycle, oxaliplatin (per label) for first 6 cycles, and leucovorin (per label) and 5-fluorouracil (per label) once every 14-days.
干预措施: leucovorin (Drug)
Arm 6
Participants will receive calderasib daily oral dose. Additionally, participants receive an intravenous infusion of cetuximab (per label) every 2 weeks of each 28-day cycle, oxaliplatin (per label) for first 6 cycles, and leucovorin (per label) and 5-fluorouracil (per label) once every 14-days.
干预措施: 5-fluorouracil (Drug)
Arm 3
Participants will receive alternate formulation of calderasib until progressive disease or discontinuation. Dosing regimen may be adjusted based on safety.
干预措施: Calderasib (Drug)
Arm 6
Participants will receive calderasib daily oral dose. Additionally, participants receive an intravenous infusion of cetuximab (per label) every 2 weeks of each 28-day cycle, oxaliplatin (per label) for first 6 cycles, and leucovorin (per label) and 5-fluorouracil (per label) once every 14-days.
干预措施: Calderasib (Drug)
Arm 5
Participants will receive calderasib daily oral dose plus an intravenous infusion of cetuximab (per label) every 2 weeks of each 28-day cycle.
干预措施: Calderasib (Drug)
Arm 4
Participants will receive calderasib daily oral dose plus an intravenous infusion of pembrolizumab (200 mg) once every 21-day cycle for up to 35 cycles (up to ~24 months). Participants will also receive carboplatin (per label) and pemetrexed (per label) once every 21-day cycle for the first 4 cycles.
干预措施: pemetrexed (Drug)
Arm 2
Participants will receive calderasib daily oral escalating dose of up to 800 mg plus pembrolizumab given as a 200 mg intravenous infusion once every 21-day cycle up to a total of 35 cycles (up to ~24 months). Treatment with calderasib will continue until progressive disease or discontinuation. Dosing regimen may be adjusted based on safety.
干预措施: Calderasib (Drug)
Arm 6
Participants will receive calderasib daily oral dose. Additionally, participants receive an intravenous infusion of cetuximab (per label) every 2 weeks of each 28-day cycle, oxaliplatin (per label) for first 6 cycles, and leucovorin (per label) and 5-fluorouracil (per label) once every 14-days.
干预措施: oxaliplatin (Drug)
Arm 6
Participants will receive calderasib daily oral dose. Additionally, participants receive an intravenous infusion of cetuximab (per label) every 2 weeks of each 28-day cycle, oxaliplatin (per label) for first 6 cycles, and leucovorin (per label) and 5-fluorouracil (per label) once every 14-days.
干预措施: cetuximab (Biological)
结局指标
主要结局
Number of Participants Who Discontinue Study Treatment Due to an AE
时间窗: Up to ~56 months
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. The number of participants who discontinue study treatment due to an AE will be reported.
Number of Participants Who Experience an Adverse Event (AE)
时间窗: Up to ~56 months
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. The number of participants who experience an AE will be reported.
Number of Participants Who Experience a Dose-Limiting Toxicity (DLT)
时间窗: Up to ~21 days
A DLT is defined as an event with toxicity including the type, severity, time of onset, time of resolution, and the probable association with study treatment that are not due to pre-existing conditions as defined by the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE 5.0). Number of participants who experience a DLT will be reported.
次要结局
- Objective Response Rate (ORR)(Up to ~56 months)
- Duration of Response (DOR)(Up to ~56 months)
- Mean Plasma Concentration of calderasib(At designated timepoints during the study in Cycles 1, 2, 3, 5, 9, 13, 17, 21, 25, and every 6 weeks thereafter up to 56 months. Cycle=3 weeks (Arms 1-4) and 4 weeks (Arms 5-6))
- Maximum Concentration (Cmax) of calderasib(At designated timepoints during the study in Cycles 1, 2, 3, 5, 9, 13, 17, 21, 25, and every 6 weeks thereafter up to 56 months. Cycle=3 weeks (Arms 1-4) and 4 weeks (Arms 5-6).)
- Time to Maximum Concentration (Tmax) of calderasib(At designated timepoints during the study in Cycles 1, 2, 3, 5, 9, 13, 17, 21, 25, and every 6 weeks thereafter up to 56 months. Cycle=3 weeks (Arms 1-4) and 4 weeks (Arms 5-6))
- Minimum Concentration (Cmin) of calderasib(At designated timepoints during the study in Cycles 1, 2, 3, 5, 9, 13, 17, 21, 25, and every 6 weeks thereafter up to 56 months. Cycle=3 weeks (Arms 1-4) and 4 weeks (Arms 5-6))
- Area Under the Concentration Time-Curve 0-12 Hours (AUC 0-12) of calderasib(At designated timepoint during the study in Cycle 1 Day 1: Predose and up to 12 hours postdose. Cycle=3 weeks (Arms 1-4) and 4 weeks (Arms 5-6))
- Area Under the Concentration Time-Curve 0-24 Hours (AUC 0-24) of calderasib(At designated timepoint during the study in Cycle 1 Day 1: Predose and up to 24 hours postdose. Cycle=3 weeks (Arms 1-4) and 4 weeks (Arms 5-6))
- Half-Life (t1/2) of calderasib(At designated timepoint during the study in Cycle 1 Day 1: Predose and up to 24 hours postdose. Cycle=3 weeks (Arms 1-4) and 4 weeks (Arms 5-6))