Clinical Trials Register

Summary
EudraCT Number:	2016-003934-25
Sponsor's Protocol Code Number:	MK-3475-412
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-01-30
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

Austria - BASG

A.2

EudraCT number

2016-003934-25

A.3

Full title of the trial

A Randomized Phase III study of pembrolizumab given concomitantly with chemoradiation and as maintenance therapy versus chemoradiation alone in subjects with locally advanced head and neck squamous cell carcinoma (KEYNOTE-412)

A.3.1

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

Pembrolizumab or placebo in combination with chemoradiation (CRT) in subjects with locally advanced HNSCC

A.3.2

Name or abbreviated title of the trial where available

Pembrolizumab or placebo in combination with chemoradiation in subjects with locally advanced HNSCC

A.4.1

Sponsor's protocol code number

MK-3475-412

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 LLC
B.5.2	Functional name of contact point	Global Clinical Trial Operations
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, NJ
B.5.3.3	Post code	07065
B.5.3.4	Country	United States
B.5.4	Telephone number	+1267305 0261
B.5.6	E-mail	behzad.bidadi@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.3.10	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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Cisplatin Teva® 1mg/ml
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.1	Product name	Cisplatin
D.3.4	Pharmaceutical form	Concentrate for 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	cisplatin
D.3.9.1	CAS number	15663-27-1
D.3.9.3	Other descriptive name	Cisplatin
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	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
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

Locally advanced head and neck squamous cell carcinoma (LA HNSCC)

E.1.1.1

Medical condition in easily understood language

Locally advanced head and neck squamous cell carcinoma

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10067821
E.1.2	Term	Head and neck cancer
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 Event-free survival (EFS) in subjects treated with pembrolizumab in combination with CRT and subjects treated with placebo in combination with CRT.

E.2.2

Secondary objectives of the trial

-To compare Overall Survival (OS) in subjects treated with pembrolizumab in combination with CRT and subjects treated with placebo in combination with CRT.
-To evaluate and compare the safety and tolerability profile of pembrolizumab in combination with CRT and subjects treated with placebo in combination with CRT.
- To compare mean change from baseline in Global health status/quality of life (QoL) and physical functioning using the EORTC QLQ-C30, and swallowing, speech and pain symptoms using the EORTC QLQ-H&N35 in subjects treated with pembrolizumab in combination with CRT and subjects treated with placebo in combination with CRT.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Have a pathologically proven new diagnosis of squamous cell carcinoma of:
a. Oropharyngeal p16 positive
i. T4 (N0-N3), M0 ; or
ii. N3 (T1-T4), M0
OR
b. Oropharyngeal p16 negative
i. any T3-4 (N0-N3), M0 ; or
ii. any N2a-3 (T1-T4), M0
OR
c. Larynx/hypopharynx/oral cavity (independent of p16)
i. any T3-4 (N0-N3), M0 ; or
ii. any N2a-3 (T1-T4), M0
2. Be willing and able to provide documented informed consent for the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
3. Have results from (local) testing of HPV status for oropharyngeal cancer defined as p16 IHC testing using CINtec® p16 Histology assay and a 70% cutoff point. If HPV status was previously tested using this method, no additional testing is required.
4. Have provided tissue for PD-L1 biomarker analysis from a core or
excisional biopsy (fine needle aspirate [FNA] is not adequate). If an
excisional or incisional biopsy has been performed, subjects remain
eligible for the study provided the residual disease meets the staging
criteria required for the trial (e.g., excisional biopsy of a lymph node
with residual T4 primary). Prior surgical debulking, including
tonsillectomy, for the head and neck cancer under study is not allowed.
5. Be ≥18 years of age on day of signing informed consent.
6. Have evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by CT scan or MRI, based on RECIST version 1.1.
7. Be eligible for definitive CRT and not considered for primary surgery based on investigator decision.
8. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 performed within 10 days of treatment initiation.
9. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of trial treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
10. Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in the protocol, for the course of the study through 180 days after the last dose of study medication.
11. Male subjects of childbearing potential must agree to use an adequate method of contraception as outlined in the protocol, starting with the first dose of study therapy through 180 days after the last dose of study therapy.
12. Demonstrate adequate organ function as defined in the protocol. All screening labs should be performed within 10 days of treatment initiation. All screening labs should be performed within 10 days prior to treatment initiation and assessed prior to randomizing the subject.

E.4

Principal exclusion criteria

1. Has current participation or treatment with an investigational agent or use of an investigational device within 4 weeks of the first dose of trial treatment.
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137 or other immune checkpoint inhibitors) or has previously participated in Merck MK-3475 clinical trials.
3. Has received a live vaccine within 30 days prior to the first dose of study treatment.
4. Has cancer outside of the oropharynx, larynx, and hypopharynx or oral cavity, such as nasopharyngeal, sinus, other para-nasal, or other unknown primary HNC.
5. Has had prior systemic therapy, targeted therapy, radiotherapy treatment or radical surgery for the head and neck cancer under study.
6. Has Grade ≥2 audiometric hearing loss. Note: Audiometric abnormalities without corresponding clinical symptoms of Grade ≥2 hearing loss will not be grounds for exclusion.
7. Has Grade ≥2 neuropathy.
8. Has Grade 3-4 bleeding due to the underlying malignancy.
9. If subject has received major surgery, and the subject has not
recovered adequately from the toxicity and/or complications from the intervention prior to starting trial treatment.
10. Has known active Hepatitis B (e.g., HBsAg reactive) or C (e.g., HCV RNA [qualitative] is detected).
11. Has known history of Human Immunodeficiency Virus (HIV) (HIV-1/2 antibodies).
12. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Corticosteroid use as pre-medication for allergic reactions (e.g. IV contrast), or as a prophylactic management of adverse events related to the chemotherapies specified in the protocol is allowed. A short course of steroids may be used as concomitant medication for either treatment of an adverse event or medical condition with Sponsor approval.
13. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
14. Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
15. Has history of a diagnosed and/or treated hematologic or primary solid tumor malignancy, unless in remission for at least 5 years prior to randomization. A T1-2 prostatic cancer Gleason score ≤6, superficial bladder cancer, non melanomatous skin cancer or carcinoma in situ of the cervix is eligible. Other exceptions may be considered with Sponsor consultation.
16. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
17. Has had previous allogeneic tissue/solid organ transplant.
18. Has active infection requiring systemic therapy.
19. Has a history of severe hypersensitivity reaction (e.g., generalized rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to pembrolizumab, Cisplatin or radiotherapy or their analogs.
20. Is a female subject who is pregnant or breast feeding or expecting to conceive or a male expecting to have children within the projected treatment phase of the trial, starting with the screening visit through 180 days after the last dose of trial treatment.
21. Have severe comorbidities that, in the opinion of the Investigator, might hamper participation in the study and/or the treatment administration.
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
23. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

E.5 End points

E.5.1

Primary end point(s)

Event-free survival (EFS)

E.5.1.1

Timepoint(s) of evaluation of this end point

• The interim efficacy analyses will be performed when 75% of the final required EFS events (or approximately 214 events) have accrued, which is expected approximately 33 months after study start
• The final analysis will be performed when 286 EFS events have accrued, which is estimated to be 48 months after study start.
• The interim safety analysis will be performed when the first 30 subjects have completed CRT. The eDMC will also review safety data periodically in the study.

E.5.2

Secondary end point(s)

Overall survival

E.5.2.1

Timepoint(s) of evaluation of this end point

The OS in all subjects will be evaluated at the interim or final analysis if the statistical criterion for success is met for the primary EFS hypothesis in all subjects.

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

Yes

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

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

Australia

Brazil

Canada

Colombia

Israel

Japan

Korea, Republic of

New Zealand

Taiwan

United States

Austria

France

Poland

Netherlands

Spain

Czechia

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

E.8.9.2

In all countries concerned by the trial days

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:

700

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

430

F.4.2.2

In the whole clinical trial

780

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)

Subjects who discontinue trial treatment for a reason other than centrally verified disease progression will move into the Post-Treatment Follow-Up Phase and should be assessed every 4 months for Follow-Up Years 1-2 and every 6 months for Follow-Up Years 3-5 by radiologic imaging to monitor disease status.

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

2017-03-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-02-04

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

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