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)

• ClinicalTrials.gov Identifier: NCT05067283
• Recruitment Status: Recruiting
• First Posted: October 5, 2021
• Last Update Posted: June 7, 2023
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: October 1, 2021
• First Posted Date: October 5, 2021
• Last Update Posted Date: June 7, 2023
• Actual Study Start Date: December 17, 2021
• Estimated Primary Completion Date: August 19, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 30, 2023)

• 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.
• 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.
• 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.

Original Primary Outcome Measures (submitted: October 1, 2021)

• Number of participants who experienced 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.
• Number of participants who experienced an adverse event (AE) [ Time Frame: Up to ~50 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 experienced an AE will be reported.
• Number of participants who discontinued study treatment due to an AE [ Time Frame: Up to ~50 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 discontinued study treatment due to an AE will be reported.

Current Secondary Outcome Measures (submitted: May 30, 2023)

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Original Secondary Outcome Measures (submitted: October 1, 2021)

• Objective response rate (ORR) [ Time Frame: Up to ~50 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) [ Time Frame: Up to ~50 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 was 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 have demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. The DOR as assessed by the investigator will be reported.
• Maximum plasma concentration (Cmax) of MK-1084 [ Time Frame: Pre-dose and 1, 2, 4 and 8 hours post-dose on Cycle 1 Day 1 and Cycle 2 Day 1; Pre-dose on Cycle 1 Day 2, Cycle 1 Day 15, Cycle 2 Day 2, Cycle 3 Day 1, Cycle 6 Day 1 and Day 1 of every third cycle (up to ~50 months). Each cycle = 21 days ]
  Cmax of MK-1084 determined by blood samples collected pre-dose and at designated timepoints post-dose will be reported.
• Area under the plasma concentration-time curve (AUC) of MK-1084 [ Time Frame: Pre-dose and 1, 2, 4 and 8 hours post-dose on Cycle 1 Day 1 and Cycle 2 Day 1; Pre-dose on Cycle 1 Day 2, Cycle 1 Day 15, Cycle 2 Day 2, Cycle 3 Day 1, Cycle 6 Day 1 and Day 1 of every third cycle (up to ~50 months). Each cycle = 21 days ]
  AUC of MK-1084 determined by blood samples collected pre-dose and at designated timepoints post-dose will be reported.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Advanced Solid Tumors

Intervention

• 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
• Biological: cetuximab
  Per label
• Drug: oxaliplatin
  Per label
• Drug: leucovorin
  Per label
• Drug: 5-fluorouracil
  Per label

Study Arms

• 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.
  Intervention: Drug: MK-1084
• 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.
  Interventions:

  • Drug: MK-1084
  • Biological: Pembrolizumab
• Experimental: Arm 3
  Participants will receive alternate formulation of MK-1084 until progressive disease or discontinuation. Dosing regimen may be adjusted based on safety.
  Intervention: Drug: MK-1084
• 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.
  Interventions:

  • Drug: MK-1084
  • Biological: Pembrolizumab
  • Drug: carboplatin
  • Drug: pemetrexed
• 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.
  Interventions:

  • Drug: MK-1084
  • Biological: cetuximab
• 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.
  Interventions:

  • Drug: MK-1084
  • Biological: cetuximab
  • Drug: oxaliplatin
  • Drug: leucovorin
  • Drug: 5-fluorouracil

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 25, 2023): 450
• Original Estimated Enrollment (submitted: October 1, 2021): 185
• Estimated Study Completion Date: August 19, 2026
• Estimated Primary Completion Date: August 19, 2026 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: Australia, Canada, Chile, China, Israel, Japan, Korea, Republic of, New Zealand, Panama, Poland, Spain, Switzerland, Turkey, United States

Administrative Information

• NCT Number: NCT05067283
• Other Study ID Numbers: 1084-001; MK-1084-001 ( Other Identifier: Merck ); jRCT2041220034 ( Registry Identifier: jRCT ); 2021-004024-15 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: June 2023