A Study of MK-1084 in KRAS Mutant Advanced Solid Tumors (MK-1084-001)

Phase 1

Recruiting

• Conditions: Advanced Solid Tumors
• Interventions: Drug: MK-1084; Biological: Pembrolizumab; Biological: cetuximab; Drug: oxaliplatin; Drug: carboplatin; Drug: leucovorin; Drug: pemetrexed; Drug: 5-fluorouracil

• Registration Number: NCT05067283
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

This is a study evaluating the safety, pharmacokinetics, and efficacy of MK-1084 alone, and MK-1084 plus other combination therapies in participants with advanced solid tumors with identified kirsten rat sarcoma viral oncogene homolog G12C (KRAS G12C) mutation.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2021-10-01
• Study First Submitted QC: 2021-10-01
• Study First Posted: 2021-10-05
• Study Start: 2021-12-17
• Status Verified: 2025-06
• Last Update Submitted: 2025-06-18
• Last Update Posted: 2025-06-19
• Primary Completion: 2030-02-25
• Study Completion: 2030-02-25

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 830

Inclusion Criteria

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

For Arm 2

• 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%

For Arm 3

• 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 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

Arm 5 only

• 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

Arm 6 only

• Locally advanced unresectable or metastatic colorectal adenocarcinoma with histologically or blood-based confirmation of KRAS G12C mutation

Exclusion Criteria

• 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
• Has received live or live-attenuated vaccine within 4 weeks of study start

Arm 4 Only

• 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 4	Pembrolizumab	Participants will receive MK-1084 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.
Arm 3	MK-1084	Participants will receive alternate formulation of MK-1084 until progressive disease or discontinuation. Dosing regimen may be adjusted based on safety.
Arm 5	MK-1084	Participants will receive MK-1084 daily oral dose plus an intravenous infusion of cetuximab (per label) every 2 weeks of each 28-day cycle.
Arm 6	oxaliplatin	Participants will receive MK-1084 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.
Arm 1	MK-1084	Participants will receive daily oral escalating doses of up to 800 mg of MK-1084 until progressive disease or discontinuation. Dosing regimen may be adjusted based on safety.
Arm 6	MK-1084	Participants will receive MK-1084 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.
Arm 4	carboplatin	Participants will receive MK-1084 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.
Arm 6	leucovorin	Participants will receive MK-1084 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.
Arm 2	MK-1084	Participants will receive MK-1084 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 MK-1084 will continue until progressive disease or discontinuation. Dosing regimen may be adjusted based on safety.
Arm 4	MK-1084	Participants will receive MK-1084 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.
Arm 2	Pembrolizumab	Participants will receive MK-1084 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 MK-1084 will continue until progressive disease or discontinuation. Dosing regimen may be adjusted based on safety.
Arm 4	pemetrexed	Participants will receive MK-1084 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.
Arm 5	cetuximab	Participants will receive MK-1084 daily oral dose plus an intravenous infusion of cetuximab (per label) every 2 weeks of each 28-day cycle.
Arm 6	cetuximab	Participants will receive MK-1084 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.
Arm 6	5-fluorouracil	Participants will receive MK-1084 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.

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Discontinue Study Treatment Due to an AE	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)	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)	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.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	Up to ~56 months	ORR is defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). The percentage of participants who experience a CR or PR as assessed by the investigator based on RECIST 1.1 will be reported.
Duration of Response (DOR)	Up to ~56 months	DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. The DOR as assessed by the investigator will be reported.
Time to Maximum Concentration (Tmax) of MK-1084	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)	Tmax of MK-1084 determined by blood samples collected pre-dose and at designated timepoints post-dose will be reported.
Minimum Concentration (Cmin) of MK-1084	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)	Cmin of MK-1084 determined by blood samples collected pre-dose and at designated timepoints post-dose will be reported.
Area Under the Concentration Time-Curve 0-12 Hours (AUC 0-12) of MK-1084	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)	AUC 0-12 of MK-1084 determined by blood samples collected pre-dose and at designated timepoints post-dose will be reported.
Area Under the Concentration Time-Curve 0-24 Hours (AUC 0-24) of MK-1084	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)	AUC 0-24 of MK-1084 determined by blood samples collected pre-dose and at designated timepoints post-dose will be reported.
Half-Life (t1/2) of MK-1084	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 MK-1084 determined by blood samples collected pre-dose and at designated timepoints post-dose will be reported.
Mean Plasma Concentration of MK-1084	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)	Mean Plasma Concentration of MK-1084 determined by blood samples collected pre-dose and at designated timepoints post-dose will be reported.
Maximum Concentration (Cmax) of MK-1084	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).	Cmax of MK-1084 determined by blood samples collected pre-dose and at designated timepoints post-dose will be reported.

Trial Locations

Locations (69)

Moffitt Cancer Center ( Site 0261); 🇺🇸 Tampa, Florida, United States

START Midwest ( Site 0267); 🇺🇸 Grand Rapids, Michigan, United States

John Theurer Cancer Center at Hackensack University Medical Center ( Site 0260); 🇺🇸 Hackensack, New Jersey, United States

Laura and Isaac Perlmutter Cancer Center ( Site 0270); 🇺🇸 New York, New York, United States

NEXT Virginia ( Site 0271); 🇺🇸 Fairfax, Virginia, United States

MEDICAL COLLEGE OF WISCONSIN-Cancer Center Clinical Trials Office ( Site 0262); 🇺🇸 Milwaukee, Wisconsin, United States

Chris O'Brien Lifehouse ( Site 0002); 🇦🇺 Camperdown, New South Wales, Australia

Liverpool Hospital-Medical Oncology ( Site 0001); 🇦🇺 Liverpool, New South Wales, Australia

Westmead Hospital ( Site 0006); 🇦🇺 Westmead, New South Wales, Australia

Monash Health-Oncology Research ( Site 0003); 🇦🇺 Clayton, Victoria, Australia

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