Pembrolizumab (MK-3475) Plus Gemcitabine/Cisplatin Versus Placebo Plus Gemcitabine/Cisplatin for First-Line Advanced and/or Unresectable Biliary Tract Carcinoma (BTC) (MK-3475-966/KEYNOTE-966)

Study Overview
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Brief Summary
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This is a study of pembrolizumab plus gemcitabine/cisplatin versus placebo plus gemcitabine/cisplatin as first-line therapy in participants with advanced and/or unresectable biliary tract carcinoma. The primary hypothesis is pembrolizumab plus gemcitabine/cisplatin is superior to placebo plus gemcitabine/cisplatin with respect to overall survival (OS).

Official Title
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A Phase 3 Randomized, Double Blind Study of Pembrolizumab Plus Gemcitabine/Cisplatin Versus Placebo Plus Gemcitabine/Cisplatin as First-Line Therapy in Participants With Advanced and/or Unresectable Biliary Tract Carcinoma

Conditions
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Biliary Tract Carcinoma

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Gemcitabine
* Drug: Cisplatin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Has histologically confirmed diagnosis of advanced (metastatic) and/or unresectable (locally advanced) biliary tract cancer (intra-or extrahepatic cholangiocarcinoma or gallbladder cancer) Has measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1), as determined by the site investigator Participants with a history of hepatitis B or hepatitis C can be enrolled if they meet study criteria Is able to provide archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion Has a life expectancy of greater than 3 months Has adequate organ function Exclusion Criteria Has had previous systemic therapy for advanced (metastatic) or unresectable (locally advanced) biliary tract cancer (intra-or extra hepatic cholangiocarcinoma or gallbladder cancer) Has ampullary cancer Has small cell cancer, neuroendocrine tumors, lymphoma, sarcoma, mixed tumor histology and/or mucinous cystic neoplasms Has received prior therapy with an anti-programmed cell death 1 (anti-PD-1), anti- programmed cell death ligand 1 or 2 (anti-PD-L1, anti-PD-L2) agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX-40, CD137) Has a known history of, or any evidence of, central nervous system (CNS) metastases and/or carcinomatous meningitis, as assessed by local site investigator 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (Pembrolizumab+Gemcitabine+Cisplatin)<br>Pembrolizumab, 200 mg, every 3 weeks (Q3W), Day 1 of each 3-week cycle for up to 35 cycles PLUS Gemcitabine, 1000 mg/m^2, Q3W, Day 1 and Day 8 of each cycle until progressive disease or unacceptable toxicity PLUS Cisplatin, 25 mg/m^2, Q3W, Day 1 and Day 8 of each cycle for up to 8 cycles. | Biological: Pembrolizumab<br>* Pembrolizumab by intravenous (IV) infusion<br>* Other names: MK-3475;Drug: Gemcitabine<br>* Gemcitabine by IV infusion<br>* Other names: Gemzar;Drug: Cisplatin<br>* Cisplatin by IV infusion<br>* Other names: Platinol®-AQ;|
| Placebo Comparator: Arm B (Placebo+Gemcitabine+Cisplatin)<br>Placebo to Pembrolizumab, 200 mg, every 3 weeks (Q3W), Day 1 of each 3-week cycle for up to 35 cycles PLUS Gemcitabine, 1000 mg/m^2, Q3W, Day 1 and Day 8 of each cycle until progressive disease or unacceptable toxicity PLUS Cisplatin, 25 mg/m^2, Q3W, Day 1 and Day 8 of each cycle for up to 8 cycles. | Drug: Gemcitabine<br>* Gemcitabine by IV infusion<br>* Other names: Gemzar;Drug: Cisplatin<br>* Cisplatin by IV infusion<br>* Other names: Platinol®-AQ;Drug: Placebo<br>* Placebo to pembrolizumab<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival was defined as the time from randomization to death due to any cause. | Up to approximately 38 months | 

Secondary 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 Response Evaluation Criteria in Solid Tumors Version 1.1 (BICR) | PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 by BICR, or death due to any cause, whichever occurred first. | Up to approximately 26 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) | ORR was defined as the percentage of participants who have a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: a ≥30% decrease in the sum of diameters [SOD] of target lesions) as assessed by BICR per RECIST 1.1, which was adjusted for this study to allow a maximum of 10 target lesions in total and 5 per organ. | Up to approximately 26 months | 
| Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR | For participants who demonstrate a confirmed CR or PR, DOR was the time from the first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurred first. | Up to approximately 38 months | 
| Number of Participants Who Experience One or More Adverse Events (AE) | An adverse event (AE) was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study. | Up to approximately 38 months | 
| Number of Participants Who Discontinued Study Intervention Due to an Adverse Event (AE) | An AE was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurs during the course of the study. | Up to approximately 38 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed cell death 1 (PD-1), Pembrolizumab, Cholangiocarcinoma, Gallbladder cancer, Checkpoint inhibitor, Immunotherapy, Biliary, Keytruda, Bile Duct Cancer