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)-China Extension Study

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

In this China Extension study, pembrolizumab plus gemcitabine/cisplatin will be compared with placebo plus gemcitabine/cisplatin as first-line therapy in Chinese adults 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).

Study Overview

• Status: Completed
• Conditions: Biliary Tract Carcinoma
• Intervention / Treatment: Biological: Pembrolizumab; Drug: Gemcitabine; Drug: Cisplatin; Drug: Placebo

Detailed Description

The China extension study will include participants previously enrolled in China in the global study for MK-3475-966 (NCT04003636) plus those enrolled during the China extension enrollment period. A total of approximately 158 Chinese participants will be enrolled.

• Study Type: Interventional
• Enrollment (Actual): 158
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China, 230001
      • Anhui Provincial Hospital ( Site 0140)
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100036
      • Beijing Cancer Hospital ( Site 0138)
    • Beijing, Beijing Municipality, China, 100730
      • Peking Union Medical College Hospital ( Site 0150)
  • Chongqing Municipality
    • Chongqing, Chongqing Municipality, China, 400038
      • First Affiliated Hospital of The Third Military Medical University ( Site 0130)
  • Fujian
    • Fuzhou, Fujian, China, 350014
      • Fujian Provincial Cancer Hospital ( Site 0154)
    • Fuzhou, Fujian, China, 350025
      • 900 Hospital of the Joint ( Site 0137)
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • Guangdong Provincial People s Hospital ( Site 0161)
  • Heilongjiang
    • Harbin, Heilongjiang, China, 610000
      • Harbin Medical University Cancer Hospital ( Site 0133)
  • Hunan
    • Changsha, Hunan, China, 410005
      • Hunan Provincial People Hospital ( Site 0142)
    • Changsha, Hunan, China, 410013
      • Hunan Cancer Hospital ( Site 0132)
    • Changsha, Hunan, China, 410013
      • The Third Xiangya Hospital of Central South University ( Site 0157)
  • Jiangsu
    • Nanjing, Jiangsu, China, 210031
      • The 81st Hospital of PLA ( Site 0128)
  • Jilin
    • Changchun, Jilin, China, 130021
      • The First Hospital of Jilin University ( Site 0131)
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 200032
      • Zhongshan Hospital Fudan University ( Site 0129)
    • Shanghai, Shanghai Municipality, China, 200127
      • Renji Hospital Shanghai Jiaotong University School of Medicine ( Site 0158)
    • Shanghai, Shanghai Municipality, China, 201315
      • Fudan University Shanghai Cancer Center ( Site 0160)
  • Shanxi
    • Xi’an, Shanxi, China, 710038
      • Tangdu Hospital ( Site 0146)
    • Xi’an, Shanxi, China, 710048
      • The First Affiliated Hospital of Xi an Jiaotong University ( Site 0145)
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • West China Hospital of Sichuan University ( Site 0147)
  • Tianjin Municipality
    • Tianjin, Tianjin Municipality, China, 300060
      • Tianjin Medical University Cancer Institute & Hospital ( Site 0155)
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310003
      • The First Affiliated Hospital Zhejiang University ( Site 0136)
    • Hangzhou, Zhejiang, China, 310022
      • Zhejiang Cancer Hospital ( Site 0134)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Pembrolizumab + Chemotherapy; Participants receive pembrolizumab, 200 mg intravenous (IV) infusion, every 3 weeks (Q3W), Day 1 of each 3-week cycle for up to 35 cycles PLUS gemcitabine, 1000 mg/m^2, IV infusion Q3W, Day 1 and Day 8 of each 3-week cycle until progressive disease or unacceptable toxicity PLUS cisplatin, 25 mg/m^2 IV infusion, Q3W, Day 1 and Day 8 of each 3-week cycle for up to 8 cycles. Eligible participants who stop the initial course of pembrolizumab with stable disease (SD) or better but progress after discontinuation will initiate a second course of pembrolizumab 200 mg IV Q3W, Day 1 of each 3-week cycle for up to 17 cycles. Treatment with gemcitabine can be stopped at any time in first or second course due to toxicity or disease progression.	Biological: Pembrolizumab; Pembrolizumab by intravenous (IV) infusion; Other Names: MK-3475; Drug: Gemcitabine; Gemcitabine by IV infusion; Other Names: Gemzar; Drug: Cisplatin; Cisplatin by IV infusion; Other Names: Platinol®; Platinol®-AQ
Placebo Comparator: Arm B: Placebo + Chemotherapy; Participants receive placebo to pembrolizumab, 200 mg IV infusion, every 3 weeks (Q3W), Day 1 of each 3-week cycle for up to 35 cycles PLUS gemcitabine, 1000 mg/m^2 IV infusion, Q3W, Day 1 and Day 8 of each 3-week cycle until progressive disease or unacceptable toxicity PLUS cisplatin, 25 mg/m^2 IV infusion, Q3W, Day 1 and Day 8 of each 3-week cycle for up to 8 cycles.	Drug: Gemcitabine; Gemcitabine by IV infusion; Other Names: Gemzar; Drug: Cisplatin; Cisplatin by IV infusion; Other Names: Platinol®; Platinol®-AQ; Drug: Placebo; Placebo to pembrolizumab by IV infusion

What is the study measuring?

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. Per protocol the final reported outcome for OS did not include any sensitivity or supportive analysis.	Up to approximately 29 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 BICR	PFS was defined as the time from randomization to the first documented disease progression (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PFS as assessed by BICR per RECIST 1.1 was presented.	Up to approximately 29 months
Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR	ORR was defined as the percentage of participants who had 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 29 months
Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR	For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of a CR or PR until PD or death. DOR for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least a 5 mm in the sum of diameters. The appearance of one or more new lesions was also considered PD. DOR assessments were based on BICR with confirmation. The DOR as assessed using RECIST 1.1 for all participants who experienced a confirmed CR or PR was presented.	Up to approximately 29 months
Number of Participants Who Experienced One or More Adverse Events (AEs)	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. Number of participants who experienced one or more AEs was reported.	Up to approximately 29 months
Number of Participants Who Discontinued Study Intervention Due to an 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 occurred during the course of the study. Number of participants who discontinued study intervention (includes any study medication given during the study) due to an AE were reported.	Up to approximately 29 months

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Yoo C, Ueno M, Klumpen HJ, Kelley RK, Vogel A, Furuse J, Ren Z, Yau T, Chan SL, Ozaka M, Oh SC, Gu S, Park JO, Valle JW, Edeline J, Kim JG, Kamble S, Norquist JM, Yu L, Malhotra U, Finn RS. Health-related quality of life in participants with advanced biliary tract cancer from the randomized phase III KEYNOTE-966 study. J Hepatol. 2025 Sep;83(3):692-700. doi: 10.1016/j.jhep.2025.03.019. Epub 2025 Mar 27.

Helpful Links

• Merck Clinical Trials Information
• Plain Language Summary

Study record dates

Study Major Dates

• Study Start (Actual): July 10, 2020
• Primary Completion (Actual): December 15, 2022
• Study Completion (Actual): March 25, 2025

Study Registration Dates

• First Submitted: June 8, 2021
• First Submitted That Met QC Criteria: June 8, 2021
• First Posted (Actual): June 11, 2021

Study Record Updates

• Last Update Posted (Actual): April 15, 2026
• Last Update Submitted That Met QC Criteria: April 2, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Checkpoint inhibitor; Immunotherapy; Pembrolizumab; Keytruda; Cholangiocarcinoma; Gallbladder cancer; Biliary; Programmed cell death 1 (PD-1); Bile Duct Cancer
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Biliary Tract Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Carcinoma; Bile Duct Diseases; Gallbladder Diseases; Biliary Tract Neoplasms; Cholangiocarcinoma; Bile Duct Neoplasms; Gallbladder Neoplasms; Parkinson Disease 4, Autosomal Dominant Lewy Body; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Platinum Compounds; Gemcitabine; Cisplatin; pembrolizumab
• Other Study ID Numbers: 3475-966 China Extension; MK-3475-966 (Other Identifier: MSD); KEYNOTE-966 (Other Identifier: MSD); 195007 (Registry Identifier: JAPIC-CTI)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes