Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Cancer MedDRA version: 21.0 Level: PT Classification code 10010035 Term: Colorectal cancer stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.1 Level: LLT Classification code 10079619 Term: MSI-high System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: MK-1308A (Coformulated MK 1308/MK 3475)
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: quavonlimab
Current Sponsor code: MK-1308
Other descriptive name: MK-1308
Concentr
Sponsors
Merck Sharp & Dohme LLC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Has a histologically confirmed diagnosis of Stage IV CRC adenocarcinoma (as defined by AJCC version 8). 2. Has locally confirmed dMMR/MSI-H. Cohort A: 3. Has been previously treated for their disease and radiographically progressed per RECIST 1.1 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: a) Fluoropyrimidine, irinotecan and oxaliplatin. b) With or without an anti-VEGF monoclonal antibody (eg, bevacizumab) c) At least one of the anti-EGFR monoclonal antibodies (cetuximab or panitumumab) for RAS WT participants with left-sided tumors. Prior EGFR therapy is optional for patients with right sided RAS WT tumors. Cohort B: 4. Has untreated Stage IV dMMR/MSI-H CRC with no prior chemotherapy or immunotherapy for this disease. 5. Is male or female and at least 18 years of age at the time of providing documented informed consent. 6. Has a life expectancy of at least 3 months. 7. Has ECOG Performance Status of 0 to 1 at Screening and within 3 days before Cycle 1 Day 1 treatment. 8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: • Not a WOCBP OR • A WOCBP and uses a contraceptive method that is highly effective (with a failure rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (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. The investigator should evaluate the potential for contraceptive method failure in relationship to the first dose of study intervention. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Has a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours for a urine test or 72 hours for a serum test before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. Abstains from breastfeeding during the study intervention period and for at least 120 days after study intervention. Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a woman with an early undetected pregnancy. 9. The participant (or legally acceptable representative) has provided documented informed consent/assent for the study. The participant may also provide consent/assent for FBR. However, the participant may participate in the study without participating in FBR. 10. Have measurable disease per RECIST 1.1 as assessed by the site and verified by BICR. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions. 11. Submit an archival (within 5 years of Screening) or newly obtained tumor tissue sample that has not been previously irradiated; FFPE blocks are preferred to slides. If a sufficient specimen does not exist, the participant must be willing to undergo a core or excisional biopsy during Screening. Newly obtained biopsies are preferred to archived tissue. For Cohort A, sampl
Exclusion criteria
Exclusion criteria: 1. Has received prior therapy with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, PD 1, CTLA-4, OX-40, CD137, PD-L1, ILT-4, LAG-3, TIGIT). 2. Has received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention. 3. If the participant had a surgery and they have not recovered adequately from the procedure and/or any complications from the surgery before starting study intervention. 4. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=2 weeks of radiotherapy) to non-CNS disease. 5. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. 6. 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. 7. 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. 8. Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. 9. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, (ie, without evidence of progression) for at least 4 weeks by repeat imaging, clinically stable and without requirement of steroid treatment for at least 14 days before the first dose of study intervention. 10. Has severe hypersensitivity (=Grade 3) to pembrolizumab, quavonlimab, favezelimab, vibostolimab, MK-4830, and/or any of their excipients. 11. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. Exception: Participants with a history of inflammatory bowel disease (eg, Crohn’s disease or ulcerative colitis) may not participate, regardless of treatment history. 12. Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis. 13. Has a history of acute or chronic pancreatitis. 14. Has neuromuscular disorders associated with an elevated creatine kinase (eg, inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy). 15. Has urine protein =1 g/24h. 16. Has an active infection requiring systemic therapy (eg, tuberculosis, known viral or bacterial infections, etc.). 17. Has a known history of HIV infection. 18. Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and active Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection. 19. 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 failu
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. Objective (Cohort A): To compare MK-1308A and pembrolizumab with respect to Objective Response Rate (ORR) per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR) 2. Objective (Cohort B): To compare MK-1308A, MK-4280A, MK-7684A, MK-4830+Pembrolizumab, and pembrolizumab monotherapy with respect to ORR per RECIST 1.1 as assessed by BICR;Secondary Objective: 1. Cohorts A, B: To evaluate DOR per RECIST 1.1 as assessed by BICR 2. Cohort A: MK-1308A versus(vs) pembrolizumab with respect to Progression-Free Survival(PFS) per RECIST 1.1 by BICR and investigator 3. Cohort B: To compare MK-1308A, MK-4280A, MK-7684A, MK-4830+Pembrolizumab, and pembrolizumab with respect to PFS per RECIST 1.1 by BICR and investigator 4. Cohort A: MK-1308A vs pembrolizumab with respect to ORR per RECIST 1.1 by investigator 5. Cohort B: To compare MK-1308A, MK-4280A, MK-7684A, MK-4830+Pembrolizumab, and pembrolizumab with respect to ORR per RECIST 1.1 by investigator 6. Cohort A: MK-1308A vs pembrolizumab with respect to Overall Survival(OS) 7. Cohort B: To compare MK-1308A, MK-4280A, MK-7684A, MK-4830+Pembrolizumab, and pembrolizumab with respect to OS 8. Cohort A: To evaluate the safety and tolerability of MK-1308A vs pembrolizumab 9. Cohort B: To evaluate the safety and tolerability of MK-1308A, MK-4280A, MK-7684A, MK-4830+Pembrolizumab, and pembrolizumab;Primary end point(s): 1. Cohort A: 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) 2. Cohort B: ORR per RECIST 1.1 as assessed by BICR ;Timepoint(s) of evaluation of this end point: 1. Up to approximately 50 months 2. Up to approximately 50 months | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Cohorts A and B: Duration of Response (DOR) per RECIST 1.1 as assessed by BICR 2. Cohort A: Progression-Free Survival (PFS) per RECIST 1.1 as assessed by BICR 3. Cohort B: PFS per RECIST 1.1 as assessed by BICR 4. Cohort A: PFS per RECIST 1.1 as assessed by investigator 5. Cohort B: PFS per RECIST 1.1 as assessed by investigator 6. Cohort A: ORR per RECIST 1.1 as assessed by investigator 7. Cohort B: ORR per RECIST 1.1 as assessed by investigator 8. Cohorts A and B: DOR per RECIST 1.1 as assessed by investigator 9. Cohort A: Overall Survival (OS) 10. Cohort B: OS 11. Cohort A: Number of participants who experienced an Adverse Event (AE) 12. Cohort A: Number of participants discontinuing study treatment due to an AE 13. Cohort B: Number of participants who experienced an AE 14. Cohort B: Number of participants discontinuing study treatment due to an AE ;Timepoint(s) of evaluation of this end point: 1. Up to approximately 50 months 2. Up to approximately 50 months 3. Up to approximately 50 months 4. Up to approximately 50 months 5. Up to approximately 50 months 6. Up to approximately 50 months 7. Up to approximately 50 months 8. Up to approximately 50 months 9. Up to approximately 50 months 10. Up to approximately 50 months 11. Up to approximately 50 months 12. Up to approximately 50 months 13. Up to approximately 50 months 14. Up to approximately 50 months | — |
Countries
Belgium, Canada, Denmark, France, Germany, Greece, Hungary, Italy, Korea, Republic of, Lithuania, Netherlands, Poland, Russian Federation, Spain, Turkey, United Kingdom, United States
Contacts
Public ContactGCTO
Merck Sharp & Dohme LLC
Outcome results
None listed