A Multi Arm Study in Participants with MSI-High Metastatic Colorectal Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

23 Jun 2021 → ongoing

Decision date (initial)

2023-09-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck Sharp & Dohme LLC

External identifiers

EU CT number

2022-502100-70-00

EudraCT number

2020-005114-18

WHO UTN

U1111-1283-2434

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenetic, Therapy, Pharmacokinetic, Safety, Pharmacodynamic, Efficacy, Pharmacogenomic

1. Objective (Cohort A): To compare MK-1308A and pembrolizumab monotherapy with respect to Objective Response Rate per RECIST 1.1 as assessed by Blinded Independent Central Review
2. Objective (Cohort B): To compare MK-1308A, MK-4280A, MK-7684A, MK-4830+Pembrolizumab, and pembrolizumab monotherapy with respect to Objective Response Rate per RECIST1.1 as assessed by Blinded Independent Central Review

Secondary objectives 12

1. Objective (Cohorts A and B): To evaluate Duration of Response per RECIST 1.1 as assessed by Blinded Independent Central Review
2. Objective (Cohort A): To compare MK-1308A and pembrolizumab monotherapy with respect to Progression-Free Survival per RECIST 1.1 as assessed by Blinded Independent Central Review
3. Objective (Cohort B): To compare MK-1308A, MK-4280A, MK-7684A, MK-4830+Pembrolizumab, and pembrolizumab monotherapy with respect to Progression-Free Survival per RECIST 1.1 as assessed by Blinded Independent Central Review
4. Objective (Cohort A): To compare MK-1308A and pembrolizumab monotherapy with respect to Progression-Free Survival per RECIST 1.1 as assessed by the investigator
5. Objective (Cohort B): To compare MK-1308A, MK-4280A, MK-7684A, MK-4830+Pembrolizumab, and pembrolizumab monotherapy with respect to Progression-Free Survival per RECIST 1.1 as assessed by the investigator
6. Objective (Cohort A): To compare MK-1308A and pembrolizumab monotherapy with respect to Objective Response Rate per RECIST 1.1 as assessed by the investigator
7. Objective (Cohort B): To compare MK-1308A, MK-4280A, MK-7684A, MK-4830+Pembrolizumab, and pembrolizumab monotherapy with respect to Objective Response Rate per RECIST 1.1 as assessed by the investigator
8. Objective (Cohort A and B): To evaluate Duration of Response per RECIST 1.1 as assessed by the investigator
9. Objective (Cohort A): To compare MK-1308A and pembrolizumab monotherapy with respect to Overall Survival
10. Objective (Cohort B): To compare MK-1308A, MK-4280A, MK-7684A, MK-4830+Pembrolizumab, and pembrolizumab monotherapy with respect to Overall Survival
11. Objective (Cohort A): To evaluate the safety and tolerability of MK-1308A compared to pembrolizumab monotherapy
12. Objective (Cohort B): To evaluate the safety and tolerability of MK-1308A, MK-4280A, MK-7684A, MK-4830+Pembrolizumab, and compared to pembrolizumab monotherapy

Conditions and MedDRA coding

Participants with Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Cancer

Regulatory references

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Has a histologically confirmed diagnosis of Stage IV Colorectal Cancer (CRC) adenocarcinoma (as defined by American Joint Committee on Cancer [AJCC] version 8)
2. Has locally confirmed Mismatch Repair Deficient (dMMR) /Microsatellite Instability-High (MSI-H)
3. Has a life expectancy of at least 3 months
4. 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
5. Has measurable disease per RECIST 1.1 as assessed by the site and verified by BICR
6. 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
7. Has adequate organ function
8. 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.
9. Cohort B: • Has untreated Stage IV dMMR/MSI-H CRC with no prior chemotherapy or immunotherapy for this disease

Exclusion criteria 23

1. Has received prior therapy with an agent directed to another stimulatory or coinhibitory T-cell receptor
2. Has received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention
3. Has not recovered adequately from a surgery procedure, and/or has any complications from a prior surgery before starting study intervention
4. Has received prior radiotherapy within 2 weeks of start of study intervention
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 central nervous system (CNS) metastases and/or carcinomatous meningitis
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 (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
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
15. Has urine protein ≥1 gram/24 hours
16. Has an active infection requiring systemic therapy (e.g., tuberculosis, known viral or bacterial infections, etc.)
17. Has a known history of Human Immunodeficiency Virus (HIV) infection
18. 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
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 failure. Medically controlled arrhythmia stable on medication is permitted
20. Has present or progressive accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks before randomization/allocation
21. 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
22. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
23. Has had an allogenic tissue/solid organ transplant

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

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)

Secondary endpoints 8

1. Duration of Response (DOR) per RECIST 1.1 as assessed by BICR
2. Progression-Free Survival (PFS) per RECIST 1.1 as assessed by BICR
3. PFS per RECIST 1.1 as assessed by Investigator
4. ORR per RECIST 1.1 as assessed by Investigator
5. DOR per RECIST 1.1 as assessed by Investigator
6. Overall Survival (OS)
7. Number of Participants Who Experienced an Adverse Event (AE)
8. Number of Participants Discontinuing Study Treatment Due to an AE

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

David Fogelman

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

David Fogelman

Third parties 4

Locations

13 EU/EEA countries · 47 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 165 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

11 submissions — initial application plus substantial / non-substantial modifications