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A Study of MK-1084 as Monotherapy and in Combination With Pembrolizumab (MK-3475) in Participants With KRAS G12C Mutant Advanced Solid Tumors (MK-1084-001)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05067283
Recruitment Status : Recruiting
First Posted : October 5, 2021
Last Update Posted : June 7, 2023
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Study Description
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Brief Summary:
This is a study evaluating the efficacy, safety, and pharmacokinetics of MK-1084 in participants with advanced solid tumors with identified kirsten rat sarcoma viral oncogene homolog G12C (KRAS G12C) mutation and MK-1084 plus pembrolizumab in participants with first line (1L) non-small cell lung cancer (NSCLSC) with identified KRAS G12C mutation.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Drug: MK-1084 Biological: Pembrolizumab Drug: carboplatin Drug: pemetrexed Biological: cetuximab Drug: oxaliplatin Drug: leucovorin Drug: 5-fluorouracil Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 450 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1, Open-Label, Multicenter Study to Assess Safety, Tolerability, PK, and Efficacy of MK-1084 as Monotherapy and in Combination With Pembrolizumab in Subjects With KRAS G12C Mutant Advanced Solid Tumors
Actual Study Start Date : December 17, 2021
Estimated Primary Completion Date : August 19, 2026
Estimated Study Completion Date : August 19, 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm 1
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.
 Drug: MK-1084
Oral dose
Experimental: Arm 2
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.
 Drug: MK-1084
Oral dose

Biological: Pembrolizumab
Intravenous infusion of 200 mg
Other Names:
  • KEYTRUDA®
  • MK-3475
Experimental: Arm 3
Participants will receive alternate formulation of MK-1084 until progressive disease or discontinuation. Dosing regimen may be adjusted based on safety.
 Drug: MK-1084
Oral dose
Experimental: Arm 4
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.
 Drug: MK-1084
Oral dose

Biological: Pembrolizumab
Intravenous infusion of 200 mg
Other Names:
  • KEYTRUDA®
  • MK-3475

Drug: carboplatin
Per label

Drug: pemetrexed
Per label
Experimental: Arm 5
Participants will receive MK-1084 daily oral dose plus an intravenous infusion of cetuximab (per label) every 2 weeks of each 28-day cycle.
 Drug: MK-1084
Oral dose

Biological: cetuximab
Per label
Experimental: Arm 6
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.
 Drug: MK-1084
Oral dose

Biological: cetuximab
Per label

Drug: oxaliplatin
Per label

Drug: leucovorin
Per label

Drug: 5-fluorouracil
Per label


Outcome Measures
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Primary Outcome Measures :
  1. Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) [ Time Frame: 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.

  2. Number of Participants Who Experience an Adverse Event (AE) [ Time Frame: 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.

  3. Number of Participants Who Discontinue Study Treatment Due to an AE [ Time Frame: 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.


Secondary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: 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.

  2. Duration of Response (DOR) [ Time Frame: 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.

  3. Mean Plasma Concentration of MK-1084 [ Time Frame: 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.

  4. Maximum Concentration (Cmax) of MK-1084 [ Time Frame: 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.

  5. Time to Maximum Concentration (Tmax) of MK-1084 [ Time Frame: 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.

  6. Minimum Concentration (Cmin) of MK-1084 [ Time Frame: 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.

  7. Area Under the Concentration Time-Curve 0-12 Hours (AUC 0-12) of MK-1084 [ Time Frame: 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.

  8. Area Under the Concentration Time-Curve 0-24 Hours (AUC 0-24) of MK-1084 [ Time Frame: 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.

  9. Half-Life (t1/2) of MK-1084 [ Time Frame: 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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

For all participants:

  • Has measurable disease by RECIST 1.1 criteria
  • Has adequate organ function
  • Male participants must be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent OR must agree to use contraception unless confirmed to be azoospermic
  • Female participants must not be pregnant or breastfeeding, and at least one of the following conditions applies: is not a woman of child-bearing potential (WOCBP); is a WOCBP and uses a contraceptive method that is highly effective, with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle 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: 3L/4L metastatic colorectal cancer (mCRC)
  • Has histologically or cytologically confirmed diagnosis of unresectable and metastatic colorectal adenocarcinoma with histological or blood-based confirmation of KRAS G12C mutation
  • Previous treatment failure of 2 or 3 previous lines 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

- Untreated 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)
  • 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
  • Has a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
  • 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
Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05067283


Contacts
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Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com

Locations
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Sponsors and Collaborators
Merck Sharp & Dohme LLC
Investigators
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Study Director: Medical Director Merck Sharp & Dohme LLC
More Information
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Additional Information:

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Responsible Party: Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier: NCT05067283    
Other Study ID Numbers: 1084-001
MK-1084-001 ( Other Identifier: Merck )
jRCT2041220034 ( Registry Identifier: jRCT )
2021-004024-15 ( EudraCT Number )
First Posted: October 5, 2021    Key Record Dates
Last Update Posted: June 7, 2023
Last Verified: June 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms
Leucovorin
Carboplatin
Pembrolizumab
Fluorouracil
Oxaliplatin
Pemetrexed
Cetuximab
Antineoplastic Agents
Antineoplastic Agents, Immunological
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites
 Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antidotes
Protective Agents
Vitamin B Complex
Vitamins
Micronutrients
Enzyme Inhibitors
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors