Biliary Tract Carcinoma
Conditions
Keywords
Programmed cell death 1 (PD-1), Pembrolizumab, Cholangiocarcinoma, Gallbladder cancer, Checkpoint inhibitor, Immunotherapy, Biliary, Keytruda, Bile Duct Cancer
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).
Interventions
BIOLOGICALPembrolizumab
Pembrolizumab by intravenous (IV) infusion
DRUGGemcitabine
Gemcitabine by IV infusion
DRUGCisplatin
Cisplatin by IV infusion
DRUGPlacebo
Placebo to pembrolizumab
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to approximately 38 months | Overall survival was defined as the time from randomization to death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Up to approximately 26 months | 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. |
| 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) | 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 | Up to approximately 38 months | 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. |
| Number of Participants Who Experience One or More Adverse Events (AE) | Up to approximately 65 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 experienced one or more AEs were reported. |
| Number of Participants Who Discontinued Study Intervention Due to an AE | Up to approximately 63 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. Number of participants who discontinued study intervention due to an AE were reported. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Chile, China, France, Germany, Hong Kong, Ireland, Israel, Italy, Japan, Malaysia, Netherlands, New Zealand, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Pre-assignment details
Per protocol, response or progression during the second course treatment was not counted towards efficacy outcome measures, and adverse events during the second course treatment were not counted towards safety outcome measures.
Participants by arm
| Arm | Count |
|---|---|
| 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. Participants in Arm A who stopped study intervention after achieving stable-disease (SD) or better may have been eligible to receive additional pembrolizumab for up to 17 cycles if they experienced radiographic disease progression while off study intervention, according to the protocol-defined criteria. Gemcitabine may have been continued until progressive disease (PD) or unacceptable toxicity during second course at investigator's discretion. | 533 |
| 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. | 536 |
| Total | 1,069 |
Baseline characteristics
| Characteristic | Total | Arm A (Pembrolizumab+Gemcitabine+Cisplatin) | Arm B (Placebo+Gemcitabine+Cisplatin) |
|---|---|---|---|
| Age, Continuous | 62.5 Years STANDARD_DEVIATION 10.7 | 63.3 Years STANDARD_DEVIATION 10.3 | 61.8 Years STANDARD_DEVIATION 11 |
| Disease Status Locally Advanced | 126 Participants | 60 Participants | 66 Participants |
| Disease Status Metastatic | 943 Participants | 473 Participants | 470 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 111 Participants | 59 Participants | 52 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 882 Participants | 433 Participants | 449 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 76 Participants | 41 Participants | 35 Participants |
| Geographic Region Asian | 486 Participants | 242 Participants | 244 Participants |
| Geographic Region Non-Asian | 583 Participants | 291 Participants | 292 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 495 Participants | 245 Participants | 250 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 11 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 7 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 25 Participants | 13 Participants | 12 Participants |
| Race (NIH/OMB) White | 524 Participants | 256 Participants | 268 Participants |
| Sex: Female, Male Female | 517 Participants | 253 Participants | 264 Participants |
| Sex: Female, Male Male | 552 Participants | 280 Participants | 272 Participants |
| Site of Origin Extrahepatic | 203 Participants | 98 Participants | 105 Participants |
| Site of Origin Gallbladder | 233 Participants | 115 Participants | 118 Participants |
| Site of Origin Intrahepatic | 633 Participants | 320 Participants | 313 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 483 / 533 | 505 / 536 | 4 / 10 |
| other Total, other adverse events | 513 / 529 | 522 / 534 | 10 / 10 |
| serious Total, serious adverse events | 280 / 529 | 264 / 534 | 0 / 10 |
Outcome results
Primary
Overall Survival (OS)
Overall survival was defined as the time from randomization to death due to any cause.
Time frame: Up to approximately 38 months
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Pembrolizumab+Gemcitabine+Cisplatin) | Overall Survival (OS) | 12.7 Months |
| Arm B (Placebo+Gemcitabine+Cisplatin) | Overall Survival (OS) | 10.9 Months |
p-value: 0.003495% CI: [0.72, 0.95]Regression, Cox
Secondary
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.
Time frame: Up to approximately 38 months
Population: All randomized participants with CR or PR
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Pembrolizumab+Gemcitabine+Cisplatin) | Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR | 9.7 Months |
| Arm B (Placebo+Gemcitabine+Cisplatin) | Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR | 6.9 Months |
Secondary
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.
Time frame: Up to approximately 38 months
Population: All Participants as Treated (APaT) population, which consisted of all randomized participants who received at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A (Pembrolizumab+Gemcitabine+Cisplatin) | Number of Participants Who Discontinued Study Intervention Due to an Adverse Event (AE) | 138 Participants |
| Arm B (Placebo+Gemcitabine+Cisplatin) | Number of Participants Who Discontinued Study Intervention Due to an Adverse Event (AE) | 122 Participants |
Secondary
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.
Time frame: Up to approximately 38 months
Population: All Participants as Treated (APaT) population, which consisted of all randomized participants who received at least 1 dose of study intervention
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A (Pembrolizumab+Gemcitabine+Cisplatin) | Number of Participants Who Experience One or More Adverse Events (AE) | 524 Participants |
| Arm B (Placebo+Gemcitabine+Cisplatin) | Number of Participants Who Experience One or More Adverse Events (AE) | 532 Participants |
Secondary
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.
Time frame: Up to approximately 26 months
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Pembrolizumab+Gemcitabine+Cisplatin) | 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) | 28.7 Percentage of Participants |
| Arm B (Placebo+Gemcitabine+Cisplatin) | 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) | 28.5 Percentage of Participants |
p-value: 0.473595% CI: [-5.2, 5.6]Miettinen & Nurminen
Secondary
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.
Time frame: Up to approximately 26 months
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Pembrolizumab+Gemcitabine+Cisplatin) | 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) | 6.5 Months |
| Arm B (Placebo+Gemcitabine+Cisplatin) | 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) | 5.6 Months |
p-value: 0.022595% CI: [0.75, 1]Regression, Cox