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Clinical Trials List

Protocol NumberMK-3475-966
NCT Number(ClinicalTrials.gov Identfier)NCT04003636
Completed

2019-09-01 - 2025-12-31

Phase III

Recruiting7

ICD-10C24.9

Malignant neoplasm of biliary tract, unspecified

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

  • Trial Applicant

    Merck Sharp & Dohme (I.A.) LLC

  • Sponsor

    Merck Sharp & Dohme Corp.

  • Trial scale

    Multi-Regional Multi-Center

  • Update

    2026/02/01

Investigators and Locations

Principal Investigator Ming-Huang Chen Division of Hematology & Oncology
Taipei Veterans General Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator 陳新炫 Division of Hematology & Oncology
Koo Foundation Sun Yat-Sen Cancer Center

Co-Principal Investigator

  • 鄭小湘 Division of Hematology & Oncology

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Li-Yuan Bai Division of Hematology & Oncology
China Medical University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Jen-Shi Chen Division of Hematology & Oncology
Linkou Chang Gung Medical Foundation

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Chia-Jui Yen Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Tai-Jan Chiu Division of Hematology & Oncology
Kaoshiung Chang Gung Memorial Hospital of the C.G.M.F.

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Chiun Hsu Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Condition/Disease

Biliary Tract Carcinoma

Objectives

Primary  Objective: To compare progression-free survival (PFS) per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR), between pembrolizumab plus gemcitabine/cisplatin and placebo plus gemcitabine/cisplatin  Objective: To compare overall survival (OS) between pembrolizumab plus gemcitabine/cisplatin and placebo plus gemcitabine/cisplatin

Test Drug

Pembrolizumab (MK-3475)

Active Ingredient

Pembrolizumab (Humanized anti-PD-1 mAb)

Dosage Form

Injection

Dosage

100 mg/ 4 mL/ vial

Endpoints

Primary Outcome Measures :
Overall Survival (OS) [ Time Frame: Up to approximately 43 months ]
Overall survival is defined as the time from randomization to death due to any cause.


Secondary Outcome Measures :
Objective Response Rate (ORR) per RECIST 1.1 as Assessed by BICR [ Time Frame: Up to approximately 43 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 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 43 months ]
For participants who demonstrate a 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.

Number of Participants Who Experience One or More Adverse Events (AE) [ Time Frame: Up to approximately 43 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 approximately 43 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.

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 approximately 43 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.

Inclution Criteria

1. Has histologically confirmed diagnosis of advanced (metastatic) and/or unresectable
(locally advanced) biliary tract cancer (intra-or extrahepatic cholangiocarcinoma or
gallbladder cancer).
2. Have measurable disease based on RECIST 1.1, as determined by the site investigator.
Lesions situated in a previously treated area by either radiotherapy, photodynamic
therapy, or arterial embolization are considered measurable if progression has been
demonstrated in such lesions and they meet criteria for measurable disease.
3. Participants with past or ongoing HCV infection are eligible for the study. Treated
participants must have completed their treatment at least 1 month prior to starting study
intervention. Untreated or incompletely treated HCV participants may initiate anti-viral
therapy for HCV if liver function remains stable for at least 3 months on study
intervention.
4. Participants with controlled hepatitis B are eligible for the study , as long as they meet the
following criteria:
 Participants with chronic HBV infection, defined as HBsAg positive and/or
detectable HBV DNA, must be given antiviral therapy for HBV for at least 4
weeks prior to the first dose of study intervention and HBV viral load must be less
than 100 IU/mL prior to first dose of study treatment. Participants on active HBV
therapy with viral loads under 100 IU/mL should stay on the same therapy
throughout study intervention. Antiviral therapy after completion of study
intervention should follow local guidelines.
 Participants with clinically resolved HBV infection, defined as HBsAg negative
and anti-HBc positive, and who have an undetectable HBV viral load at screening
should be checked every 6 weeks for HBV viral load and treated for HBV if viral
load is over 100 IU/mL. Antiviral therapy after completion of study intervention
should follow local guidelines.
Demographics
5. Is male or female, from at least 18 years of age inclusive, at the time of signing the
informed consent.
Male Participants
6. Male participants are eligible to participate if they agree to the following during the
intervention period and for at least and through 120 days after the last dose of
chemotherapy:
• Refrain from donating sperm
PLUS either:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle
(abstinent on a long term and persistent basis) and agree to remain abstinent
OR
• Must agree to use contraception unless confirmed to be azoospermic (vasectomized or
secondary to medical cause (Appendix 5), as detailed below:
◦ Agree to use a male condom plus partner use of an additional contraceptive
method when having penile-vaginal intercourse with a WOCBP who is not
currently pregnant. Note: Men with a pregnant or breastfeeding partner must
agree to remain abstinent from penile-vaginal intercourse or use a male condom
during each episode of penile-vaginal penetration.
• Male participants must also agree to use a male condom when engaging in any activity
that allows for passage of ejaculate to another person of any sex.
• Contraceptive use by men should be consistent with local regulations regarding the
methods of contraception for those participating in clinical studies.
Female Participants
7. A female participant is eligible to participate if she is not pregnant or breastfeeding, and
at least one of the following conditions applies:
- Is not a woman of childbearing potential (WOCBP)
OR
- Is a WOCBP and using a contraceptive method that is highly effective (with a failure
rate of <1% per year), with low user dependency, or be abstinent from heterosexual
intercourse as their preferred and usual lifestyle (abstinent on a long term and
persistent basis), as described in Appendix 5 during the intervention period and for at
least and through 210 days after the last dose of chemotherapy or through 120 days
after the last dose of pembrolizumab or placebo, whichever is greater, and agrees not
to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose
of reproduction during this period. The investigator should evaluate the potential for
contraceptive method failure (ie, noncompliance, recently initiated) in relationship to
the first dose of study intervention.
- A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as
required by local regulations) within 24 hours before the first dose of study
intervention.
- If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum
pregnancy test is required. In such cases, the participant must be excluded from
participation if the serum pregnancy result is positive.
• Additional requirements for pregnancy testing during and after study intervention are
located in Appendix 2.
• The investigator is responsible for review of medical history, menstrual history, and
recent sexual activity to decrease the risk for inclusion of a woman with an early
undetected pregnancy.
• Contraceptive use by women should be consistent with local regulations regarding the
methods of contraception for those participating in clinical studies.
Informed Consent
8. The participant (or legally acceptable representative, if applicable) provides written
informed consent for the study. The participant may also provide consent for future
biomedical research. However, the participant may enroll in the main study without
participating in future biomedical research.
Additional Categories
9. Have a performance status of 0 or 1 on the ECOG Performance Scale within 3 days prior
to the first dose of study intervention.
10. Provide archival tumor tissue sample or newly obtained core or excisional biopsy of a
tumor lesion not previously irradiated (ie, obtained for histological confirmation) for
biomarker analysis. The tumor tissue must be received by the central vendor and be
deemed adequate for biomarker analysis evaluation prior to participant randomization.
Formalin-fixed, paraffin-embedded (FFPE) tissue blocks are preferred to slides. Newly
obtained biopsies are preferred to archived tissue.
Note: Details pertaining to tumor tissue submission can be found in the laboratory
manual.
11. Have a life expectancy of greater than 3 months.
12. Have adequate organ function, as defined in the following table (Table 3). Specimens
must be collected within 14 days prior to the first dose of study intervention.

Exclusion Criteria

Medical Conditions
1. Has had previous systemic therapy for advanced (metastatic) or unresectable (locally
advanced) biliary tract cancer (intra-or extra hepatic cholangiocarcinoma or gallbladder
cancer), with the exception of adjuvant therapy which is allowed. Adjuvant therapy
should have been completed at least 6 months prior to diagnosis of advanced and/or
unresectable disease.
2. Has ampullary cancer.
3. Has small cell cancer, neuroendocrine tumors, lymphoma, sarcoma and/or Mucinous
cystic neoplasms.
4. Has an active autoimmune disease that has required systemic treatment in the past 2 years
(ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
treatment and is allowed.
5. Has undergone major surgery and has not recovered adequately from the toxicity to
≤Grade 1 and/or complications from the intervention prior to starting study intervention.
6. A WOCBP who has a positive urine pregnancy test within 24 hours prior to
administration of study intervention (see Appendix 5). If the urine test is positive or
cannot be confirmed as negative, a serum pregnancy test will be required.
Note: In the event that 24 hours have elapsed between the screening pregnancy test and
the first dose of study intervention, another pregnancy test (urine or serum) must be
performed and must be negative in order for the participant to start receiving study
intervention.
Prior/Concomitant Therapy
7. 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 co-inhibitory T-cell receptor (eg, CTLA-4, OX40, CD137).
8. Has received prior anti-cancer therapy for advanced unresectable biliary tract cancer
(intra-or extra hepatic cholangiocarcinoma or gallbladder cancer), including
investigational agents within 4 weeks prior to randomization.
9. Has not recovered (ie, AE ≤Grade 1 or baseline) from AEs due to previously
administered chemotherapy. Participants with ≤Grade 2 neuropathy may be eligible
based on investigator assessment.
10. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants
must have recovered from all radiation-related toxicities, not require corticosteroids, and
have not had radiation pneumonitis. A 1-week washout is permitted for palliative
radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
11. Has received a live vaccine within 30 days prior to the first dose of study intervention.
Note: Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–
Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are
generally killed virus vaccines and are allowed; however, intranasal influenza vaccines
(eg, FluMist®) are live attenuated vaccines and are not allowed.
Prior/Concurrent Clinical Study Experience
12. Is currently participating in or has participated in a study of an investigational agent or
has used an investigational device within 4 weeks prior to the first dose of study
intervention.
Note: Participants who have entered the follow-up phase of an investigational study may
participate as long as it has been 4 weeks after the last dose of the previous
investigational agent.
Diagnostic Assessments
13. 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 intervention.
14. Has a known additional malignancy that is progressing or has required active treatment
within the past 3 years.
Note: Participants with 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.
15. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, gemcitabine, or cisplatin
and/or any of their excipients.
16. Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.
17. Has an active infection requiring systemic therapy, with the exception of HBV, and HCV.
18. Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV
infection (anti-HCV Ab (+) and detectable HCV RNA) at study entry.
19. Has a known history of human immunodeficiency virus (HIV) infection.
Note: No HIV testing is required unless mandated by local health authority.
20. Has known active tuberculosis (TB; Bacillus tuberculosis). Note: No testing for TB is
required unless mandated by local health authority.
21. Has a known history of, or any evidence of, CNS metastases and/or carcinomatous
meningitis, as assessed by local site investigator.
22. Has a history or current evidence of any condition, (eg, hearing impairment, etc.),
therapy, or laboratory abnormality that might confound the results of the study, interfere
with the participant's participation for the full duration of the study, or is not in the best
interest of the participant to participate, in the opinion of the treating investigator.
23. Has a known psychiatric or substance abuse disorder that would interfere with the
participant’s ability to cooperate with the requirements of the study.
Other Exclusions
24. Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 210 days after
the last dose of chemotherapy or through 120 days after the last dose of pembrolizumab
or placebo, whichever is greater.
25. Has had an allogenic tissue/solid organ transplant.

The Estimated Number of Participants

  • Taiwan

    35 participants

  • Global

    788 participants

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