Colorectal Cancer
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)
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.
Interventions
BIOLOGICALPembrolizumab
400 mg or 200 mg pembrolizumab administered via IV infusion.
BIOLOGICALPembrolizumab/Quavonlimab
Co-formulated pembrolizumab/quavonlimab (400 mg/25 mg) fixed-dose combination (FDC) administered via IV infusion.
BIOLOGICALPembrolizumab/Favezelimab
Co-formulated pembrolizumab/favezelimab (200 mg/800 mg) FDC administered via IV infusion
BIOLOGICALPembrolizumab/Vibostolimab
Co-formulated pembrolizumab/vibostolimab (200 mg/200 mg) FDC administered via IV infusion
BIOLOGICALMK-4830
800 mg MK-4830 administered via IV infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Up to approximately 46 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
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) per RECIST 1.1 as assessed by BICR | Up to approximately 46 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. |
| Progression-Free Survival (PFS) per RECIST 1.1 as assessed by BICR | Up to approximately 46 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. |
| PFS per RECIST 1.1 as assessed by Investigator | Up to approximately 46 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. |
| ORR per RECIST 1.1 as assessed by Investigator | Up to approximately 46 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. |
| DOR per RECIST 1.1 as assessed by Investigator | Up to approximately 46 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. |
| Overall Survival (OS) | Up to approximately 46 months | OS is defined as the time from randomization (or first dose) to death due to any cause. OS will be presented. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to approximately 60 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. |
| Number of Participants Discontinuing Study Treatment Due to an AE | Up to approximately 60 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. |
Countries
Belgium, Canada, Colombia, Costa Rica, Denmark, Estonia, France, Germany, Greece, Guatemala, Hungary, Italy, Lithuania, Netherlands, Poland, Romania, Russia, South Korea, Spain, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Outcome results
None listed