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) (KEYNOTE-966)

• ClinicalTrials.gov Identifier: NCT04003636
• Recruitment Status: Active, not recruiting
• First Posted: July 1, 2019
• Results First Posted: December 22, 2023
• Last Update Posted: March 5, 2024
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: June 28, 2019
• First Posted Date: July 1, 2019
• Results First Submitted Date: December 6, 2023
• Results First Posted Date: December 22, 2023
• Last Update Posted Date: March 5, 2024
• Actual Study Start Date: September 24, 2019
• Actual Primary Completion Date: December 15, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 6, 2023)

Overall Survival (OS) [ Time Frame: Up to approximately 38 months ]

Overall survival was defined as the time from randomization to death due to any cause.

Original Primary Outcome Measures (submitted: June 28, 2019)

• Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Blinded Independent Central Review (BICR) [ Time Frame: Up to 48 months ]
  Progression-free survival is defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first. Progressive Disease (PD) is a ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of ≥20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.
• Overall Survival (OS) [ Time Frame: Up to 48 months ]
  Overall survival is defined as the time from randomization to death due to any cause.

Current Secondary Outcome Measures (submitted: December 6, 2023)

• 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) [ Time Frame: Up to approximately 26 months ]
  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.
• 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) [ Time Frame: Up to approximately 26 months ]
  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.
• Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR [ Time Frame: Up to approximately 38 months ]
  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.
• Number of Participants Who Experience One or More Adverse Events (AE) [ Time Frame: Up to approximately 38 months ]
  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 Discontinued Study Intervention Due to an Adverse Event (AE) [ Time Frame: Up to approximately 38 months ]
  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.

Original Secondary Outcome Measures (submitted: June 28, 2019)

• Objective Response Rate (ORR) per RECIST 1.1 as Assessed by BICR [ Time Frame: Up to 48 months ]
  ORR is 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 is modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
• Duration of Response (DOR) per RECIST 1.1 as Assessed by BICR [ Time Frame: Up to 48 months ]
  For participants who demonstrate confirmed CR or PR, DOR is the time from the first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first. Complete Response is the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response is a ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) is a ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of ≥20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.
• Number of Participants Who Experience One or More Adverse Events (AE) [ Time Frame: Up to 48 months ]
  An adverse event (AE) is 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 is considered related to the medical treatment or procedure, that occurs during the course of the study.
• Number of Participants Who Discontinued Study Intervention Due to an Adverse Event [ Time Frame: Up to 48 months ]
  An AE is 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 is considered related to the medical treatment or procedure, that occurs during the course of the study.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• Official Title: 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
• Brief Summary: 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Biliary Tract Carcinoma

Intervention

• Biological: Pembrolizumab
  Pembrolizumab by intravenous (IV) infusion
  Other Name: MK-3475
• Drug: Gemcitabine
  Gemcitabine by IV infusion
  Other Name: Gemzar
• Drug: Cisplatin
  Cisplatin by IV infusion
  Other Names:

  • Platinol®
  • Platinol®-AQ
• Drug: Placebo
  Placebo to pembrolizumab

Study Arms

• Experimental: Arm A (Pembrolizumab+Gemcitabine+Cisplatin)
  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.
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Gemcitabine
  • Drug: Cisplatin
• Placebo Comparator: Arm B (Placebo+Gemcitabine+Cisplatin)
  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.
  Interventions:

  • Drug: Gemcitabine
  • Drug: Cisplatin
  • Drug: Placebo

• Publications *: Kelley RK, Ueno M, Yoo C, Finn RS, Furuse J, Ren Z, Yau T, Klumpen HJ, Chan SL, Ozaka M, Verslype C, Bouattour M, Park JO, Barajas O, Pelzer U, Valle JW, Yu L, Malhotra U, Siegel AB, Edeline J, Vogel A; KEYNOTE-966 Investigators. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 Jun 3;401(10391):1853-1865. doi: 10.1016/S0140-6736(23)00727-4. Epub 2023 Apr 16. Erratum In: Lancet. 2023 Sep 16;402(10406):964. Lancet. 2024 Mar 23;403(10432):1140.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 11, 2023): 1069
• Original Estimated Enrollment (submitted: June 28, 2019): 788
• Estimated Study Completion Date: November 29, 2024
• Actual Primary Completion Date: December 15, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Canada, Chile, China, France, Germany, Hong Kong, Ireland, Israel, Italy, Japan, Korea, Republic of, Malaysia, Netherlands, New Zealand, Spain, Taiwan, Thailand, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT04003636
• Other Study ID Numbers: 3475-966; MK-3475-966 ( Other Identifier: Merck ); KEYNOTE-966 ( Other Identifier: Merck ); 195007 ( Registry Identifier: JAPIC-CTI ); 2019-000944-82 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: March 2024