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)

Merck Sharp & Dohme (MSD)

Status and phase: Active, not recruiting; Phase 2

Conditions: Colorectal Cancer

Treatments: Biological: MK-4830; Biological: Pembrolizumab/Quavonlimab; Biological: Pembrolizumab; Biological: Pembrolizumab/Vibostolimab; Biological: Pembrolizumab/Favezelimab

Study type: Interventional

Funder types: Industry

Identifiers

NCT04895722

2022-502100-70 (Other Identifier)

KEYSTEP-008 (Other Identifier)

MK-1308A-008 (Other Identifier)

1308A-008

2020-005114-18 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 320 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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320 participants in 5 patient groups

Pembrolizumab

Active Comparator group

Description:

Participants receive pembrolizumab 400 mg intravenously (IV) every 6 weeks (Q6W) for up to approximately 2 years.

Treatment:

Biological: Pembrolizumab

Pembrolizumab/Quavonlimab

Experimental group

Description:

Participants receive co-formulated pembrolizumab/quavonlimab (400 mg/25 mg) Q6W for up to approximately 2 years.

Treatment:

Biological: Pembrolizumab/Quavonlimab

Pembrolizumab/Favezelimab

Experimental group

Description:

Participants receive co-formulated pembrolizumab/favezelimab (200 mg/800 mg) every 3 weeks (Q3W) for up to approximately 2 years.

Treatment:

Biological: Pembrolizumab/Favezelimab

Pembrolizumab/Vibostolimab

Experimental group

Description:

Participants receive co-formulated pembrolizumab/vibostolimab (200 mg/200 mg) Q3W for up to approximately 2 years.

Treatment:

Biological: Pembrolizumab/Vibostolimab

Pembrolizumab Plus MK-4830

Experimental group

Description:

Participants receive pembrolizumab 200 mg plus MK-4830 800 mg Q3W for up to approximately 2 years.

Treatment:

Biological: Pembrolizumab

Biological: MK-4830