Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Chinese Participants With Stage IV Colorectal Cancer (MK-3475-C66)

Study Overview
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Brief Summary
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In this study, Chinese participants with MSI-H or dMMR advanced colorectal cancer will be assigned to receive either pembrolizumab or the Investigator's choice of 1 of 6 standard of care (SOC) chemotherapy regimens for treatment. There is no hypothesis testing for this study.

Official Title
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A Phase 3 Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Chinese Participants With Stage IV Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Colorectal Cancer (MK-3475-C66)

Conditions
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Colorectal Neoplasms

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Oxaliplatin
* Drug: Leucovorin
* Drug: 5-fluorouracil
* Drug: Irinotecan
* Biological: Bevacizumab
* Biological: Cetuximab


Participation Criteria
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Eligibility Criteria
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The main inclusion and exclusion criteria include but are not limited to the following: Inclusion Criteria: Has a histologically confirmed diagnosis of colorectal adenocarcinoma that is at stage IV (as defined by American Joint Committee on Cancer eighth edition) [National Comprehensive Cancer Network 2018] Has centrally confirmed MSI-H/dMMR status Has centrally confirmed RAS and BRAF mutation status A woman of child-bearing potential (WOCBP) must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours for urine or within 72 hours for serum before the first dose of study intervention. Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology Must provide an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 3 days before randomization. Has a life expectancy of at least 3 months Exclusion Criteria: Has received prior systemic therapy for stage IV colorectal cancer (CRC). Participants may have received prior adjuvant/neoadjuvant chemotherapy for CRC as long as it was completed at least 6 months prior to randomization Has undergone major operation within 4 weeks of randomization or has not adequately recovered from major surgery or has ongoing surgical complications Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], tumor necrosis factor receptor superfamily, member 4 [OX 40], tumor necrosis factor receptor superfamily member 9 [CD137]) Has received prior radiotherapy within 2 weeks of start of study intervention or has radiation-related toxicities, requiring corticosteroids Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration. 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 5 years, with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients Has an active autoimmune disease that has required systemic treatment in past 2 years Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease Has an active infection requiring systemic therapy (eg, tuberculosis, known viral or bacterial infection) Has a known history of human immunodeficiency virus (HIV) infection Has a known history of Hepatitis B or known Hepatitis C virus infection Has had an allogenic tissue/solid organ transplant

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab<br>Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle (Q3W) for up to 35 treatments (approximately 2 years). | Biological: Pembrolizumab<br>* Intravenous (IV) infusion<br>* Other names: MK-3475;|
| Active Comparator: Standard of Care Chemotherapy<br>Participants receive 1 of 6 possible standard chemotherapy regimens at the discretion of the investigator: (1) mFOLFOX6; (2) mFOLFOX6+bevacizumab 5 mg/kg IV on Day 1 of each 14-day cycle (Q2W); (3) mFOLFOX6+cetuximab 400 mg/m^2 IV over 2 hours then 250 mg/m^2 over 1 hour weekly Q2W; (4) FOLFIRI; (5) FOLFIRI+bevacizumab 5 mg/kg IV on Day 1 Q2W; OR (6) FOLFIRI+cetuximab 400 mg/m^2 IV over 2 hours then 250 mg/m^2 over 1 hour weekly Q2W. Participants with documented disease progression following chemotherapy can receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle (Q3W) for up to 35 treatments (approximately 2 years). | Drug: Oxaliplatin<br>* 85 mg/m^2 given as an intravenous infusion (IV) on Day 1 in each 14-day cycle (Q2W) as part of the mFOLFOX6 regimen<br>Drug: Leucovorin<br>* 400 mg/m^2 given as an IV on Day 1 Q2W as part of the mFOLFOX6 and FOLFIRI regimens<br>Drug: 5-fluorouracil<br>* 400 mg/m^2 given as an IV bolus on Day 1 and then 1200 mg/m^2/day IV over 2 days for a total dose of 2400 mg/m^2 Q2W as part of the mFOLFOX6 and FOLFIRI regimens<br>* Other names: 5-FU;Drug: Irinotecan<br>* 180 mg/m^2 IV on Day 1 Q2W as part of the FOLFIRI regimen<br>Biological: Bevacizumab<br>* IV infusion<br>Biological: Cetuximab<br>* IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) For All Participants | PFS is defined as the time from randomization to the first documented disease progression (PD) per RECIST 1.1 or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥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 ≥5 mm. Note: The appearance of one or more lesions and the unequivocal progression of non-target lesions is also considered PD. The PFS per RECIST 1.1 as assessed by BICR will be reported for all participants. | Up to approximately 54 months | 
| Progression-Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) For RAS Wild-type Participants | PFS is defined as the time from randomization to the first documented disease progression (PD) per RECIST 1.1 or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥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 ≥5 mm. Note: The appearance of one or more lesions and the unequivocal progression of non-target lesions is also considered PD. The PFS per RECIST 1.1 as assessed by BICR will be reported for RAS wild-type participants . | Up to approximately 54 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) For All Participants | OS is defined as the time from randomization to death due to any cause. The OS will be reported for all participants. | Up to approximately 54 months | 
| Overall Survival (OS) For RAS Wild-type Participants | OS is defined as the time from randomization to death due to any cause. The OS will be reported for RAS wild-type participants. | Up to approximately 54 months | 
| 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) For All Participants | ORR is defined as the percentage of participants who have a best response of confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. The percentage for all participants who experience CR or PR as assessed by BICR will be presented. | Up to approximately 54 months | 
| 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) For RAS Wild-type Participants | ORR is defined as the percentage of participants who have a best response of confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. The percentage for RAS wild-type participants who experience CR or PR as assessed by BICR will be presented. | Up to approximately 54 months | 
| Number of Participants Who Experience at Least One Adverse Event (AE) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who experience an AE will be reported. | Up to approximately 54 months | 
| Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinue study treatment due to an AE will be reported. | Up to approximately 54 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death-1 (PD1, PD-1), Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1), Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)