Clinical Trials Register

Summary
EudraCT Number:	2018-001757-27
Sponsor's Protocol Code Number:	MK-3475-859
National Competent Authority:	Ireland - HPRA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-10-01
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

Ireland - HPRA

A.2

EudraCT number

2018-001757-27

A.3

Full title of the trial

A Phase 3, randomized, double-blind clinical study of pembrolizumab (MK-3475) plus chemotherapy versus placebo plus chemotherapy as first-line treatment in participants with HER2 negative, previously untreated, unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma (KEYNOTE-859)

A.3.1

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

Pembrolizumab/placebo plus chemotherapy as first-line therapy in participants with HER2 negative advanced gastric or GEJ adenocarcinoma

A.3.2

Name or abbreviated title of the trial where available

Pembrolizumab/placebo plus chemo as 1L therapy in HER2- Gastric/GEJ

A.4.1

Sponsor's protocol code number

MK-3475-859

A.5.4

Other Identifiers

Name:

Other indentification

Number:

123 482

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
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 LLC
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 (UK) Limited
B.5.2	Functional name of contact point	Global Clinical Trial Operations
B.5.3	Address:
B.5.3.1	Street Address	120 Moorgate
B.5.3.2	Town/ city	London
B.5.3.3	Post code	EC2M 6UR
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01327310547
B.5.5	Fax number	01992705241
B.5.6	E-mail	lizette.gunston@msd.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

HER2 negative, previously untreated, unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma

E.1.1.1

Medical condition in easily understood language

Gastric and gastric esophageal junction (GEJ) adenocarcinoma

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	27.0
E.1.2	Level	LLT
E.1.2	Classification code	10071114
E.1.2	Term	Metastatic gastric adenocarcinoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	27.0
E.1.2	Level	LLT
E.1.2	Classification code	10058526
E.1.2	Term	Oesophageal adenocarcinoma metastatic
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To compare the overall survival (OS) of the participants following
administration of pembrolizumab versus placebo when each is combined
with chemotherapy

E.2.2

Secondary objectives of the trial

To compare the 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), following administration of
pembrolizumab versus placebo when each is combined with
chemotherapy
To compare the objective response rate (ORR) per RECIST 1.1, as
assessed by BICR, following administration of pembrolizumab versus
placebo when each is combined with chemotherapy
To compare the duration of response (DOR) per RECIST 1.1, as assessed
by BICR, following administration of pembrolizumab versus placebo
when each is combined with chemotherapy in all participants and in
participants with PD-L1-positive tumors (CPS ≥1)
To evaluate the safety and tolerability of pembrolizumab plus
chemotherapy versus placebo plus chemotherapy

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Has histologically- or cytologically-confirmed diagnosis of locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma, with known PD-L1 expression status.
2. Has HER2 negative cancer. HER2 negative is defined as: IHC (0, or 1+) or fluorescence in situ hybridization (FISH) negative (HER2:CEP17 ratio <2 with an average HER2 copy number <4.0 signals/cell). FISH can be replaced with locally available in situ hybridization (ISH) methods acceptable as per institutional guidelines (eg, DISH).
3. Is Male or Female.
4. Is at least 18 years of age at the time of signing the informed consent (or acceptable age according to local regulations, whichever is older).
5. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 95 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) 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.
6. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies
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 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), during the intervention period and for at least 180 days after the last dose of chemotherapy or 120 days after the last dose of pembrolizumab, whichever is last, 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
7. The participant (or legally acceptable representative if applicable) has provided documented informed consent for the study. The participant may also provide consent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research.
8. Has measurable disease per RECIST 1.1 as assessed by investigator assessment. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such
lesions.
9. Has provided archival tumor tissue sample or newly obtained core, incisional or excisional biopsy of a tumor lesion not previously irradiated. Formalinfixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
10. Has provided tumor tissue sample deemed adequate for PD-L1
biomarker analysis.
11. Has provided tumor tissue sample for MSI biomarker analysis.
12. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (within 3 days prior to the start of study intervention).
13. Has adequate organ function, as defined in the protocol. Specimens must be collected within 10 days prior to the start-of-study intervention.

E.4

Principal exclusion criteria

1. Has squamous cell or undifferentiated gastric cancer.
2. Has had major surgery, open biopsy, or significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgery during the course of study intervention.
3. Has pre-existing peripheral neuropathy >Grade 1.
4. Is a WOCBP who has a positive urine pregnancy test within 24 hours for urine or within 72 hours for serum prior to randomization or treatment allocation.
5. Has had previous therapy for locally advanced, unresectable and/or metastatic gastric/GEJ cancer. Participants may have received prior neoadjuvant or adjuvant therapy as long as it was completed at least 6 months prior to randomization.
6. 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).
7. Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to randomization.
8. Has received prior radiotherapy within 2 weeks prior to start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
9. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention. Administration of killed vaccines is allowed.
10. 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.
11. 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.
12. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
13. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression) for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
14. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
15. Has an active autoimmune disease that has required systemic treatment in 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) is not considered a form of systemic treatment and is allowed.
16. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
17. Has an active infection requiring systemic therapy.
18. Has a known history of human immunodeficiency virus (HIV)
infection.
19. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
20. Has a known history of active tuberculosis.
21. Has a history or current evidence of any condition (eg, known deficiency of the enzyme dihydropyrimidine dehydrogenase), 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.
22. Participants with hypokalemia (serum potassium less than the lower limit of normal).
23. Participants with hypomagnesemia (serum magnesium less than the lower limit of normal).
24. Participants with hypocalcemia (serum calcium less than the lower limit of normal).
25. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
23. 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 after the last dose of chemotherapy or through 120 days after the last dose of pembrolizumab, whichever is greater.
24. Has had an allogenic tissue/solid organ transplant

E.5 End points

E.5.1

Primary end point(s)

- Overall survival (OS), defined as the time from randomization to death due to any cause
- Progression-free Survival (PFS), defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first

E.5.1.1

Timepoint(s) of evaluation of this end point

Overall survival (OS) = time from randomization to death due to any cause; Progression-free survival (PFS) = time from randomization to the first documented disease progression per RECIST 1.1 by (blinded independent central review (BICR) or death due to any cause, whicherver occurs first

E.5.2

Secondary end point(s)

- Objective response (OR), defined as Complete response (CR) or partial response (PR)
- Duration of Response (DOR), defined as the time from first response (CR or PR) to subsequent disease progression, or death from any cause, whichever occurs first

E.5.2.1

Timepoint(s) of evaluation of this end point

- Objective Response Rate (ORR) = proportion of participants who have an overall response – complete response (CR) or partial response (PR);
- Duration of Response (DOR) =time from first response (CR or PR) to subsequent disease progression or death from any cause, whichever occurs first

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

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

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

103

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

Chile

Colombia

Guatemala

New Zealand

Peru

Switzerland

Ukraine

Hong Kong

Taiwan

Australia

Brazil

Canada

China

Israel

Japan

Korea, Republic of

Mexico

Russian Federation

South Africa

United Kingdom

United States

Czechia

Denmark

France

Germany

Hungary

Ireland

Italy

Poland

Spain

Türkiye

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

The overall study ends when the last participant completes the last study-related telephone-call or visit, withdraws from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the investigator).

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:

455

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

1087

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

756

F.4.2.2

In the whole clinical trial

1542

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)

None

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

2018-09-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-01-30

P. End of Trial
P.	End of Trial Status	Ongoing

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