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 (KEYNOTE 966)

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
shown in such lesions and they meet criteria for measurable disease per RECIST
1.1.
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:
a) 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.
b) 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.
5. Is male or female, from at least 18 years of age inclusive, at the time of
signing the
informed consent.
6. Male participants are eligible to participate if they agree to the following
during the
intervention period and for at least and through 180 days after the last dose of
chemotherapy:
a) Refrain from donating sperm
PLUS either:
b) 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
c) 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.
d) 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.
e) Contraceptive use by men should be consistent with local regulations
regarding the
methods of contraception for those participating in clinical studies.
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 72 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.
a) The investigator is responsible for review of medical history, menstrual
history, and recent sexual activity to decrease the risk for inclusion of a
women with an early undetected pregnancy.
b) Contraceptive use by women should be consistent with local regulations
regarding the methods of contraception for those participating in clinical
studies.
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.
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, including but not limited to
PD-L1 and MSI biomarker analysis, 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. Specimens
must be collected within 14 days prior to the first dose of study intervention.

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, mixed tumor
histology 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 72 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.
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, OX-
40, 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 if deemed safe by the investigator. A 2-weeks washout period is
required for a longer course of radiation (>2 weeks).
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.
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.
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 invasive 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.
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.