Clinical Trials Register

Summary
EudraCT Number:	2019-000944-82
Sponsor's Protocol Code Number:	MK-3475-966
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2019-07-24
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - PEI

A.2

EudraCT number

2019-000944-82

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Pembrolizumab or Placebo Plus Gemcitabine/Cisplatin for First-Line Advanced and/or Unresectable BTC

A.4.1

Sponsor's protocol code number

MK-3475-966

A.5.4

Other Identifiers

Name:

IND

Number:

123482

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.
B.5.2	Functional name of contact point	GCTO
B.5.3	Address:
B.5.3.1	Street Address	126 East Lincoln Avenue P.O. Box 2000
B.5.3.2	Town/ city	Rahway, New Jersey
B.5.3.3	Post code	07065
B.5.3.4	Country	United States
B.5.4	Telephone number	+1 732-594-1936
B.5.6	E-mail	usha.malhotra@merck.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Keytruda (pembrolizumab, MK-3475)
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme B.V.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PEMBROLIZUMAB
D.3.9.1	CAS number	1374853-91-4
D.3.9.2	Current sponsor code	MK-3475
D.3.9.4	EV Substance Code	SUB167136
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Advanced and/or Unresectable Biliary Tract Carcinoma (Intrahepatic, Extrahepatic, or Gallbladder)

E.1.1.1

Medical condition in easily understood language

Advanced (metastatic) and/or unresectable (locally advanced) biliary tract cancer (intra-or extrahepatic cholangiocarcinoma or gallbladder cancer). This study is treatment naïve participants

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10004655
E.1.2	Term	Biliary carcinoma
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1. To compare overall survival (OS) between pembrolizumab plus
gemcitabine/cisplatin and placebo plus gemcitabine/cisplatin

E.2.2

Secondary objectives of the trial

1. To compare progression-free survival (PFS) per Response Evaluation
Criteria in Solid Tumors Version 1.1 (RECIST 1.1), as assessed by Blinded
Independent Central Review (BICR), between pembrolizumab plus
gemcitabine/cisplatin and placebo plus gemcitabine/cisplatin
2. To compare 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), between pembrolizumab plus
gemcitabine/cisplatin and placebo plus gemcitabine/cisplatin
3. To evaluate duration of response (DOR) per Response Evaluation
Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded
Independent Central Review (BICR)
4. To evaluate the safety and tolerability profile of pembrolizumab plus
gemcitabine/cisplatin

E.2.3

Trial contains a sub-study

E.3

Principal inclusion 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. Has 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 antiviral 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
intervention. 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.
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:
• 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.
• 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.
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
the Protocol
- A WOCBP must have a negative highly sensitive pregnancy test (urine
or serum, as required by local regulations) within 24 hours (urine) or 72
hours (serum) 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.
8. The participant (or legally acceptable representative) has provided
documented informed
consent for the study.
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.
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.

E.4

Principal exclusion criteria

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
neoadjuvant/adjuvant therapy which is allowed. Neoadjuvant/adjuvant
therapy should have been completed at least 6 months prior to diagnosis
of advanced and/or unresectable disease, and participants should not
have received gemcitabine and/or cisplatin in the neoadjuvant/adjuvant
setting. Participants who received prior neoadjuvant/adjuvant therapy
with R2 postoperative pathology of the oncologic resection are excluded.
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 procedure and/or complications from the surgery prior to starting
study intervention.
6. A WOCBP who has a positive urine pregnancy test within 24 hours
prior to administration of study intervention. If the urine test is positive
or cannot be confirmed as negative, a serum pregnancy test will be
required.
7. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PDL2
agent or with an agent directed to another stimulatory or coinhibitory
T-cell receptor (eg, CTLA-4, OX- 40, CD137).
8. Has received prior anticancer therapy (eg, TACE, palliative surgery)
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 anticancer therapy. 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 noncentral nervous system (CNS) disease if
deemed safe by the investigator. A 2-week 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.
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.
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.
15. Has severe hypersensitivity (≥Grade 3) to pembrolizumab,
gemcitabine, or cisplatin and/or any of their excipients.
16. Has a history of (noninfectious) 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.
20. Has known active tuberculosis.
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 180 days (male) or 210 days (female) after the
last dose of chemotherapy or through 120 days (female) after the last
dose of pembrolizumab or placebo, whichever is greater.
25. Has had an allogenic tissue/solid organ transplant.

E.5 End points

E.5.1

Primary end point(s)

1. Overall Survival (OS)

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Up to approximately 41 months

E.5.2

Secondary end point(s)

1. Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Blinded Independent Central Review (BICR)
2. Objective Response Rate (ORR) per RECIST 1.1 as Assessed by BICR
3. Duration of Response (DOR) per RECIST 1.1 as Assessed by BICR
4. Number of Participants Who Experienced One or More Adverse Events (AEs)
5. Number of Participants Who Discontinued Study Intervention Due to an Adverse Event (AE)

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Up to approximately 41 months
2. Up to approximately 41 months
3. Up to approximately 41 months
4. Up to approximately 41 months
5. Up to approximately 41 months

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Health Utility Scores; anti-MK3475 antibody levels

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Australia

Brazil

Canada

Chile

China

Hong Kong

Israel

Japan

Korea, Republic of

Malaysia

New Zealand

Taiwan

Thailand

United States

France

Netherlands

Spain

Germany

Italy

Belgium

Ireland

Turkey

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

528

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

520

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

205

F.4.2.2

In the whole clinical trial

1048

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Upon study completion, participants are discontinued and may be enrolled in a pembrolizumab extension study.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-09-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-09-24

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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