Clinical Trials Register

Summary
EudraCT Number:	2017-004869-27
Sponsor's Protocol Code Number:	MK-3475-756
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2018-06-27
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2017-004869-27

A.3

Full title of the trial

A Randomized, Double-Blind, Phase III Study of Pembrolizumab versus Placebo in Combination with Neoadjuvant Chemotherapy and Adjuvant Endocrine Therapy for the Treatment of High-Risk Early-Stage Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative (ER+/HER2–) Breast Cancer (KEYNOTE-756)

A.3.1

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

A Clinical Trial for Newly Diagnosed High Risk ER+/HER2– (Estrogen Receptor Positive/ Human Epidermal growth factor receptor Negative) Breast Cancer

A.3.2

Name or abbreviated title of the trial where available

Phase III pembro study in high-risk early-stage ER+/HER2–breast cancer

A.4.1

Sponsor's protocol code number

MK-3475-756

A.5.4

Other Identifiers

Name:

IND number

Number:

124 442

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 Corp., 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 (UK) Ltd.
B.5.2	Functional name of contact point	Adele Steele
B.5.3	Address:
B.5.3.1	Street Address	Hertford Road
B.5.3.2	Town/ city	Hoddesdon
B.5.3.3	Post code	EN11 9BU
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01992 452 854
B.5.5	Fax number	01992705241
B.5.6	E-mail	adele.steele@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	No
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	Pembrolizumab
D.3.2	Product code	MK-3475
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	AS1
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

High-Risk Early-Stage Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative (ER+/HER2–) Breast Cancer

E.1.1.1

Medical condition in easily understood language

newly diagnosed high risk ER+/HER2– breast cancer

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	23.0
E.1.2	Level	LLT
E.1.2	Classification code	10070575
E.1.2	Term	Estrogen receptor positive breast cancer
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

To compare the rate of pathological complete response (pCR) at the time of definitive surgery, using the definition of ypT0/Tis ypN0 as assessed by the local pathologist, of pembrolizumab versus placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies.

To compare event-free survival (EFS) following administration of pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies, as determined by the investigator.

E.2.2

Secondary objectives of the trial

1.To compare:
-OS following administration of pembrolizumab and placebo, both in combination with the neoadjuvant and adjuvant therapies
-rate of pCR at definitive surgery, using ypT0 ypN0 and ypT0/Tis as assessed by local pathologist, of pembrolizumab vs placebo, both in combination with neoadjuvant therapies
-rate of pCR at definitive surgery, using ypT0/Tis ypN0, ypT0 ypN0, and ypT0/Tis as assessed by local pathologist, of pembrolizumab vs placebo, both in combination with neoadjuvant therapies in sbj with PD-L1+ tumors (CPS ≥1)
-EFS as determined by investigator and OS following administration of pembrolizumab and placebo, both in combination with neoadjuvant and adjuvant therapies, in sbj with PD-L1+ tumors (CPS ≥1)
2.To evaluate safety and tolerability of pembrolizumab plus neoadjuvant chemotherapy and adjuvant endocrine therapy, and health related quality-of-life (QoL) assessments using QLQC30 and QLQ-BR23, within and across neoadjuvant and adjuvant periods

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

1.Merck will conduct Future Biomedical Research on DNA (blood and tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.

2.Magnetic resonance imaging of the breast will be performed in approximately 150 participants with high-risk early-stage ER+/HER2– breast cancer who choose to participate for more accurate clinical staging of the primary tumor and axilla lymphadenopathy and to ensure the primary tumor and regional lymph node staging fulfil protocol-required criteria.
If a participant has consented to participating in the breast MRI, an MRI should be scheduled for 2 time points:
• At Screening (prior to first dose of study treatment)
• After completion of the neoadjuvant period (before definitive surgery)
Changes in the MRI from the baseline will be assessed by the investigator per RECIST 1.1 Magnetic resonance imaging images of the breast will be sent to a designated central imaging vendor for collection, quality review, and independent imaging review.

E.3

Principal inclusion criteria

Type of Participant and Disease Characteristics
1. Participant has a localized invasive breast ductal adenocarcinoma, confirmed by the local pathologist, that includes either T1c-T2 (tumor size ≥2 cm), clinical node stage (cN)1-cN2, or T3-T4, cN0-cN2.
2. Has centrally confirmed ER+/HER2–, Grade 3 breast cancer of ductal histology, according to the most recent American Society of Clinical Oncology/College of American Pathologist guidelines.
3. Provides a new or recently obtained core needle biopsy, consisting of multiple cores, taken from the primary breast tumor(s) for central determination of HR status (ER and progesterone receptor), HER2, grade, and PD-L1 status.
Demographics
4. Is a male or female ≥18 years of age on the day of signing informed consent.
5. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as assessed within 10 days prior to initiation of study treatment
Male participants:
6. A male participant must agree to use a contraception as detailed in Appendix 3 of the protocol during the treatment period and for at least 12 months (for participants who received cyclophosphamide) or 6 months (for participants who did not receive cyclophosphamide) after the last dose of study treatment and refrain from donating sperm during this period.
Female participants:
7. A female participant is eligible to participate if she is not pregnant , not breastfeeding, and at least one of the following conditions applies:
a.) Not a woman of childbearing potential (WOCBP)
OR
b.) A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 12 months (for participants who received cyclophosphamide) or 6 months (for participants who did not receive cyclophosphamide) after the last dose of study treatment with pembrolizumab or placebo.
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 participate in the main study without participating in future biomedical research.
Laboratory Evaluations
9. Has adequate organ function, as detailed in the protocol; all screening laboratory tests should be performed within 10 days prior to initiation of study treatment.

E.4

Principal exclusion criteria

Medical Conditions
1. Has a history of non-infectious pneumonitis that required treatment with steroids or has current pneumonitis.
2. Has breast cancer with lobular histology.
3. Has bilateral invasive breast cancer.
4. Has metastatic (Stage IV) breast cancer.
5. Has multi-centric breast cancer (presence of more than 1 tumor in different quadrants of the breast).
6. Has any of the following clinical lymph node staging per current AJCC staging criteria for breast cancer staging based on radiological and/or clinical assessment: cN3, cN3a, cN3b, or cN3c.
7. Has ER–, progesterone receptor positive breast cancer.
8. Participants who have undergone excisional biopsy of the primary tumor and/or axillary lymph nodes or have undergone sentinel lymph node biopsy prior to study treatment.
9. Has a known additional, invasive, malignancy that is progressing or required active treatment in the last 5 years.
10. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (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 treatment.
11. 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)
12. Has a known history of active tuberculosis (Bacillus tuberculosis).
13. Has an active infection requiring systemic therapy.
14. Has a history or current evidence of any condition (eg, transfusion-dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that is specifically contraindicated per the current locally-approved labeling, that might confound the results of the study, interfere with the participant’s involvement for the full duration of the study, or is not in the best interest of the participant to be involved, in the opinion of the treating investigator.
15. Has known psychiatric or substance abuse disorders that would may interfere with cooperation with the requirements of the study.
16. Has left ventricular ejection fraction (LVEF) of <50% or below the institution limit of normal, as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed at screening.
17. Has other significant cardiac disease, such as:
- History of myocardial infarction, acute coronary syndrome, or coronary angioplasty/stenting/bypass within the last 6 months;
- Congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA Class III or IV.
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. A WOCBP who has a positive urine pregnancy test within 72 hours before the first dose of study treatment. If the urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. Prior/Concomitant Therapy
21. Has received prior treatment for breast cancer.
22. 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 (e.g., CTLA-4, OX 40, CD137).
23. Has received a live vaccine within 30 days prior to the first dose of study treatment. 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), typhoid, and intranasal influenza vaccines (eg, FluMist®) vaccine.
24. Has severe hypersensitivity (≥Grade 3) to any of the components or excipients used in the study treatments.
Prior/Concurrent Clinical Study Experience
25. Is/was enrolled in a study of an investigational agent and received study therapy, or used an investigational device within 4 weeks (12 months for an investigational agent or device with anticancer or antiproliferative properties) prior to the first dose of study treatment.
Other Exclusions
26. Is pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 12 months (for participants who received cyclophosphamide) or 6 months (for participants who did not receive cyclophosphamide) after the last dose of study treatment.

E.5 End points

E.5.1

Primary end point(s)

Pathological Complete Response Rate (ypT0/Tis ypN0)
Event-Free Survival

E.5.1.1

Timepoint(s) of evaluation of this end point

After Definitive Surgery and at any point PD/recurrance occur

E.5.2

Secondary end point(s)

Overall Survival
Pathological Complete Response Rate (ypT0 ypN0)

E.5.2.1

Timepoint(s) of evaluation of this end point

After Definitive Surgery and at any point PD/recurrance occur

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

Yes

E.6.11

Pharmacogenomic

Yes

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

111

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

Belgium

Brazil

Canada

Colombia

France

Germany

Hungary

Ireland

Israel

Japan

Korea, Republic of

New Zealand

Poland

Portugal

Russian Federation

Spain

Taiwan

Ukraine

United Kingdom

United States

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