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Evaluation of Co-formulated Pembrolizumab/Quavonlimab (MK-1308A) Versus Other Treatments in Participants With Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Cancer (CRC) (MK-1308A-008/KEYSTEP-008)

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ClinicalTrials.gov Identifier: NCT04895722
Recruitment Status : Recruiting
First Posted : May 20, 2021
Last Update Posted : May 20, 2024
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Study Description
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Brief Summary:
The purpose of this study is to assess the efficacy and safety of co-formulated pembrolizumab/quavonlimab versus other treatments in participants with MSI-H or dMMR Metastatic Stage IV Colorectal Cancer.

Condition or disease Intervention/treatment Phase
Colorectal Cancer Biological: Pembrolizumab Biological: Pembrolizumab/Quavonlimab Biological: Pembrolizumab/Favezelimab Biological: Pembrolizumab/Vibostolimab Biological: MK-4830 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 320 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2, Multicenter, Multi Arm, Study to Evaluate MK-1308A (Co-formulated Quavonlimab (MK-1308)/Pembrolizumab) Versus Other Treatments in Participants With Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Cancer: (MK-1308A-008)
Actual Study Start Date : June 25, 2021
Estimated Primary Completion Date : October 20, 2025
Estimated Study Completion Date : November 18, 2025

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Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Pembrolizumab
Participants receive pembrolizumab 400 mg intravenously (IV) every 6 weeks (Q6W) for up to approximately 2 years.
 Biological: Pembrolizumab
400 mg or 200 mg pembrolizumab administered via IV infusion.
Other Names:
  • MK-3475
  • Keytruda®
Experimental: Pembrolizumab/Quavonlimab
Participants receive co-formulated pembrolizumab/quavonlimab (400 mg/25 mg) Q6W for up to approximately 2 years.
 Biological: Pembrolizumab/Quavonlimab
Co-formulated pembrolizumab/quavonlimab (400 mg/25 mg) fixed-dose combination (FDC) administered via IV infusion.
Other Name: MK-1308A
Experimental: Pembrolizumab/Favezelimab
Participants receive co-formulated pembrolizumab/favezelimab (200 mg/800 mg) every 3 weeks (Q3W) for up to approximately 2 years.
 Biological: Pembrolizumab/Favezelimab
Co-formulated pembrolizumab/favezelimab (200 mg/800 mg) FDC administered via IV infusion
Other Name: MK-4280A
Experimental: Pembrolizumab/Vibostolimab
Participants receive co-formulated pembrolizumab/vibostolimab (200 mg/200 mg) Q3W for up to approximately 2 years.
 Biological: Pembrolizumab/Vibostolimab
Co-formulated pembrolizumab/vibostolimab (200 mg/200 mg) FDC administered via IV infusion
Other Name: MK-7684A
Experimental: Pembrolizumab Plus MK-4830
Participants receive pembrolizumab 200 mg plus MK-4830 800 mg Q3W for up to approximately 2 years.
 Biological: Pembrolizumab
400 mg or 200 mg pembrolizumab administered via IV infusion.
Other Names:
  • MK-3475
  • Keytruda®

Biological: MK-4830
800 mg MK-4830 administered via IV infusion


Outcome Measures
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Primary Outcome Measures :
  1. Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR) [ Time Frame: Up to approximately 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 RECIST 1.1. ORR as assessed by BICR will be presented.


Secondary Outcome Measures :
  1. Duration of Response (DOR) per RECIST 1.1 as assessed by BICR [ Time Frame: Up to approximately 50 months ]
    DOR is defined as the time from the first documented evidence of a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 until Progressive Disease (PD) or death due to any cause, whichever occurs first, in participants demonstrating a CR or PR. 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. DOR as assessed by BICR will be presented.

  2. Progression-Free Survival (PFS) per RECIST 1.1 as assessed by BICR [ Time Frame: Up to approximately 50 months ]
    PFS is defined as the time from randomization (or first dose) to the first documented PD per RECIST 1.1 or death from any cause, whichever occurs first. 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. PFS as assessed by BICR will be presented.

  3. PFS per RECIST 1.1 as assessed by Investigator [ Time Frame: Up to approximately 50 months ]
    PFS is defined as the time from randomization (or first dose) to the first documented PD per RECIST 1.1 or death from any cause, whichever occurs first. 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. PFS as assessed by investigator will be presented.

  4. ORR per RECIST 1.1 as assessed by Investigator [ Time Frame: Up to approximately 50 months ]
    ORR is defined as the percentage of participants who have a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. ORR as assessed by investigator will be presented.

  5. DOR per RECIST 1.1 as assessed by Investigator [ Time Frame: Up to approximately 50 months ]
    DOR is defined as the time from the first documented evidence of a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 until PD or death due to any cause, whichever occurs first, in participants demonstrating a CR or PR. 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. DOR as assessed by investigator will be presented.

  6. Overall Survival (OS) [ Time Frame: Up to approximately 50 months ]
    OS is defined as the time from randomization (or first dose) to death due to any cause. OS will be presented.

  7. Number of Participants Who Experienced an Adverse Event (AE) [ Time Frame: Up to approximately 50 months ]
    An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study intervention. The number of participants with an AE will be presented.

  8. Number of Participants Discontinuing Study Treatment Due to an AE [ Time Frame: Up to approximately 50 months ]
    An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study intervention. The number of participants that discontinue study treatment due to an AE will be presented.


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:

  • Has a histologically confirmed diagnosis of Stage IV CRC adenocarcinoma (as defined by American Joint Committee on Cancer [AJCC] version 8)
  • Has locally confirmed dMMR/MSI-H
  • Has a life expectancy of at least 3 months
  • Female participants are eligible to participate if not pregnant or breastfeeding, and not a woman of childbearing potential (WOCBP), or if a WOCBP then uses a contraceptive method that is highly effective or is abstinent on a long-term and persistent basis, during the intervention period and for at least 120 days after the last dose of study intervention
  • Has measurable disease per RECIST 1.1 as assessed by the site and verified by BICR
  • Submit an archival (within 5 years of Screening) or newly obtained tumor tissue sample that has not been previously irradiated; formalin-fixed, paraffin embedded (FFPE) blocks are preferred to slides.
  • Has adequate organ function

Cohort A:

- Has been previously treated for their Stage IV dMMR/MSI-H CRC and radiographically progressed on or after or could not tolerate standard treatment, which must include all of the following agents if approved and locally available in the country where the participant is randomized:

  • Fluoropyrimidine, irinotecan and oxaliplatin (capecitabine is acceptable as equivalent to fluorouracil in prior therapy)
  • With or without an anti-vascular endothelial growth factor (VEGF) monoclonal antibody (e.g., bevacizumab)
  • At least one of the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab or panitumumab) for rat sarcoma viral oncogene homolog (RAS) wild-type participants with left-sided tumors. Prior EGFR therapy is optional for patients with right sided RAS Wild-type (WT) tumors.

Cohort B:

- Has untreated Stage IV dMMR/MSI-H CRC with no prior chemotherapy or immunotherapy for this disease

Exclusion Criteria:

  • Has received prior therapy with an agent directed to another stimulatory or coinhibitory T-cell receptor
  • Has received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention
  • Has not recovered adequately from a surgery procedure, and/or has any complications from a prior surgery before starting study intervention
  • Has received prior radiotherapy within 2 weeks of start of study intervention
  • Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
  • Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention
  • Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication
  • Has a known additional malignancy that is progressing or has required active treatment within the past 2 years
  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
  • Has severe hypersensitivity (≥Grade 3) to pembrolizumab, quavonlimab, favezelimab, vibostolimab, MK-4830, and/or any of their excipients
  • Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
  • Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis
  • Has a history of acute or chronic pancreatitis
  • Has neuromuscular disorders associated with an elevated creatine kinase
  • Has urine protein ≥1 gram/24 hours
  • Has an active infection requiring systemic therapy (e.g., tuberculosis, known viral or bacterial infections, etc.)
  • Has a known history of Human Immunodeficiency Virus (HIV) infection
  • Concurrent active Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] positive and/or detectable Hepatitis B Virus [HBV] deoxyribonucleic acid [DNA]) and Hepatitis C virus (defined as anti-HCV antibody positive and detectable HCV ribonucleic acid [RNA] infection
  • Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study intervention administration, or New York Heart Association Class III or IV congestive heart failure. Medically controlled arrhythmia stable on medication is permitted.
  • Has present or progressive accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks before randomization/allocation
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
  • Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
  • Has had an allogenic tissue/solid organ transplant
Contacts and Locations
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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): NCT04895722


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: NCT04895722    
Other Study ID Numbers: 1308A-008
MK-1308A-008 ( Other Identifier: Merck )
2022-502100-70 ( Other Identifier: EU CT )
KEYSTEP-008 ( Other Identifier: Merck )
2020-005114-18 ( EudraCT Number )
First Posted: May 20, 2021    Key Record Dates
Last Update Posted: May 20, 2024
Last Verified: May 2024
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
Keywords provided by Merck Sharp & Dohme LLC:
Programmed Cell Death-1 (PD1, PD-1)
Programmed Death-Ligand 1 (PDL1, PD-L1)
Additional relevant MeSH terms:
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Colorectal Neoplasms
Microsatellite Instability
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
 Intestinal Diseases
Rectal Diseases
Genomic Instability
Pathologic Processes
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action