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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03725059




Registration number
NCT03725059
Ethics application status
Date submitted
29/10/2018
Date registered
30/10/2018
Date last updated
9/08/2019

Titles & IDs
Public title
Study of Pembrolizumab (MK-3475) Versus Placebo in Combination With Neoadjuvant Chemotherapy & Adjuvant Endocrine Therapy in the Treatment of Early-Stage Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative (ER+/HER2-) Breast Cancer (MK-3475-756/KEYNOTE-756)
Scientific title
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)
Secondary ID [1] 0 0
2017-004869-27
Secondary ID [2] 0 0
3475-756
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - Pembrolizumab (K)
Treatment: Drugs - Placebo (P)
Treatment: Drugs - Paclitaxel (X)
Treatment: Drugs - Doxorubicin hydrochloride (A)
Treatment: Drugs - Epirubicin (E)
Treatment: Drugs - Cyclophosphamide (C)
Treatment: Drugs - Endocrine therapy
Treatment: Other - Radiation therapy
Treatment: Surgery - Surgery

Experimental: Pembrolizumab+Chemotherapy (KX/KA[E]C) - In the neoadjuvant setting, participants receive pembrolizumab (K) 200 mg via intravenous (IV) infusion once every 3 weeks (Q3W) + paclitaxel (X) 80 mg/m^2 via IV infusion once weekly (QW) for 4 cycles (Treatment 1), followed by pembrolizumab 200 mg via IV infusion + doxorubicin or epirubicin (A or E; 60 mg/m^2 or 100 mg/m^2) via IV infusion Q3W + cyclophosphamide (C) 600 mg/m^2 via IV infusion Q3W for 4 cycles (Treatment 2). At 3 to 6 weeks after last cycle of neoadjuvant treatment, participants will undergo definitive surgery for their breast cancer. After surgery, participants will begin adjuvant study treatment. In the adjuvant setting, participants receive pembrolizumab 200 mg via IV infusion Q3W for 9 cycles + variable endocrine therapy for up to 10 years. Each cycle is 21 days long.

Placebo Comparator: Placebo+Chemotherapy (PX/PA[E]C) - In the neoadjuvant setting, participants receive placebo (P; normal saline or dextrose) via IV infusion Q3W + paclitaxel (X) 80 mg/m^2 via IV infusion once weekly (QW) for 4 cycles (Treatment 1), followed by placebo via IV infusion + doxorubicin or epirubicin (A or E; 60 mg/m^2 or 100 mg/m^2) via IV infusion Q3W + cyclophosphamide (C) 600 mg/m^2 via IV infusion Q3W for 4 cycles (Treatment 2). At 3 to 6 weeks after last cycle of neoadjuvant treatment, participants will undergo definitive surgery for their breast cancer. After surgery, participants will begin adjuvant study treatment. In the adjuvant setting, participants receive placebo via IV infusion Q3W for 9 cycles + variable endocrine therapy for up to 10 years. Each cycle is 21 days long.


Other interventions: Pembrolizumab (K)
IV infusion Q3W

Treatment: Drugs: Placebo (P)
Normal saline or dextrose IV infusion Q3W

Treatment: Drugs: Paclitaxel (X)
IV infusion QW

Treatment: Drugs: Doxorubicin hydrochloride (A)
IV infusion Q3W

Treatment: Drugs: Epirubicin (E)
IV infusion Q3W

Treatment: Drugs: Cyclophosphamide (C)
IV infusion Q3W

Treatment: Drugs: Endocrine therapy
Variable endocrine therapy for up 10 years

Treatment: Other: Radiation therapy
Variable radiation therapy per local standard of care

Treatment: Surgery: Surgery
Definitive surgery for breast cancer

Intervention code [1] 0 0
Other interventions
Intervention code [2] 0 0
Treatment: Drugs
Intervention code [3] 0 0
Treatment: Other
Intervention code [4] 0 0
Treatment: Surgery
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Pathological Complete Response (pCR) Rate Using the Definition of ypT0/Tis ypN0 - The pCR rate (ypT0/Tis ypN0) is defined as the percentage of participants without residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy by American Joint Committee on Cancer (AJCC) staging criteria (7th edition) assessed by the local pathologist at the time of definitive surgery. The percentage of participants with a pathological Complete Response (pCR) using the definition of (ypT0/Tis ypN0) will be presented for pembrolizumab versus placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies.
Timepoint [1] 0 0
Up to approximately 7 months (Time of surgery)
Primary outcome [2] 0 0
Event-Free Survival (EFS) - EFS is defined as the time from randomization to disease progression that: precludes definitive surgery, results in a local or distant recurrence, results in a second primary malignancy, or death due to any cause whichever occurs first. The EFS following administration of pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies, as determined by the investigator will be presented.
Timepoint [2] 0 0
Up to approximately 10 years
Secondary outcome [1] 0 0
Overall Survival (OS) - OS is defined as the time from date of randomization to date of death due to any cause. The OS following administration of pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies will be presented.
Timepoint [1] 0 0
Up to approximately 10 years
Secondary outcome [2] 0 0
pCR Rate Using the Definition of ypT0ypN0 - pCR rate (ypT0ypN0) is defined as the percentage of participants without residual invasive or in situ cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes after completion of neoadjuvant systemic therapy by AJCC staging criteria (7th edition) assessed by the local pathologist at the time of definitive surgery. The percentage of participants with a pCR using the definition of (ypT0ypN0) will be presented for pembrolizumab versus placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies.
Timepoint [2] 0 0
Up to approximately 7 months (Time of surgery)
Secondary outcome [3] 0 0
pCR Rate Using the Definition of ypT0/Tis - pCR rate (ypT0/Tis) is defined as the percentage of participants without residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen (independent of lymph node involvement) after completion of neoadjuvant systemic therapy by AJCC staging criteria (7th edition) assessed by the local pathologist at the time of definitive surgery. The percentage of participants with a pCR using the definition of ypT0/Tis will be presented for pembrolizumab versus placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies.
Timepoint [3] 0 0
Up to approximately 7 months (Time of surgery)
Secondary outcome [4] 0 0
pCR Rate Using the Definitions of ypT0/Tis ypN0, ypT0/Tis, and ypT0 ypN0 in Participants With a Combined Positive Score [CPS] =1 - pCR rates were calculated using the definitions of ypT0/Tis ypN0, ypT0/Tis, and ypT0 ypN0 after completion of neoadjuvant systemic therapy by AJCC staging criteria (7th edition) assessed by the local pathologist at the time of definitive surgery. The percentage of participants with a pCR using the three definitions of ypT0/Tis ypN0, ypT0/Tis, and ypT0 ypN0 in participants with a CPS =1 (with a positive Programmed Cell Death-Ligand 1 [PD-L1] tumor status) will be presented for pembrolizumab versus placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies.
Timepoint [4] 0 0
Up to approximately 7 months (Time of surgery)
Secondary outcome [5] 0 0
EFS in Participants With a CPS =1 - EFS is defined as the time from randomization to disease progression that: precludes definitive surgery, results in a local or distant recurrence, results in a second primary malignancy, or death due to any cause whichever occurs first. The EFS following administration of pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies, as determined by the investigator for participants with a CPS =1 will be presented.
Timepoint [5] 0 0
Up to approximately 10 years
Secondary outcome [6] 0 0
OS in Participants With a CPS =1 - OS is defined as the time from date of randomization to date of death due to any cause. The OS following administration of pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies for participants with a CPS =1 will be presented.
Timepoint [6] 0 0
Up to approximately 10 years
Secondary outcome [7] 0 0
Number of Participants Experiencing an Adverse Event (AE) - An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience an AE while receiving pembrolizumab or placebo (including 1 month of safety follow up) will be presented.
Timepoint [7] 0 0
Up to approximately 15 months
Secondary outcome [8] 0 0
Number of Participants Experiencing a Serious Adverse Event (SAE) - An SAE is defined as any untoward medical occurrence that, at any dose: Results in death, Is life-threatening, Requires inpatient hospitalization or prolongation of existing hospitalization, Results in persistent or significant disability/incapacity or Is a congenital anomaly/birth defect. The number of participants who experience an SAE while receiving pembrolizumab or placebo (including 3 months of safety follow up) will be presented.
Timepoint [8] 0 0
Up to approximately 17 months
Secondary outcome [9] 0 0
Number of Participants Experiencing an Immune-related AE (irAE) - Some AEs that may occur in this study that are known to be related to pembrolizumab immunotherapy treatment and may include: pneumonitis, diarrhea/colitis, aspartate aminotransferase/alanine aminotransferase (AST/ALT) elevation or increased bilirubin, Type 1 diabetes mellitus or hyperglycemia, hypophysitis, hyperthyroidism, hypothyroidism, nephritis and renal dysfunction, and myocarditis. The number of participants who experience an irAE while receiving pembrolizumab or placebo (including 1 month of safety follow up) will be presented.
Timepoint [9] 0 0
Up to approximately 15 months
Secondary outcome [10] 0 0
Number of Study Treatment Discontinuations Due to AEs - The number of participants who discontinue study treatment (pembrolizumab or placebo) due to an AE will be presented.
Timepoint [10] 0 0
Up to approximately 14 months
Secondary outcome [11] 0 0
Change from Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire Core 30 (QLQ-C30) Score - The EORTC QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Individual responses for each of 28 items are given on a 4-point scale (1=Not at All to 4=Very Much), with a lower score indicating a better outcome, and responses for each of 2 items (overall health and overall quality of life) are given on a 7-point scale (1=Very poor to 7=Excellent), with a higher score indicating a better outcome. The change from Baseline to end of treatment (up to Cycle 4 Day 1) in EORTC-QLQ-C30 scores for participants will be presented.
Timepoint [11] 0 0
Baseline (Cycle 1 Day 1 in Treatment 1) and Cycles 1 and 4 Day 1 in Treatment 2 (Up to approximately 5 months) Each cycle is 21 days.
Secondary outcome [12] 0 0
Change from Baseline in EORTC Breast Cancer-Specific QoL Questionnaire (QLQ-BR23) Score - The EORTC QLQ-BR23 is a 23-item questionnaire developed to assess the quality of life in women with breast cancer. Responses for each item are given on a 4-point scale (1=Not at All to 4=Very Much), with a lower score indicating a better outcome. The change from Baseline to end of treatment (up to Cycle 4 Day 1) in EORTC QLQ-BR23 score for participants will be presented.
Timepoint [12] 0 0
Baseline (Cycle 1 Day 1 in Treatment 1) and Cycles 1 and 4 Day 1 in Treatment 2 (Up to approximately 5 months) Each cycle is 21 days.

Eligibility
Key inclusion criteria
- 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. Note: Inflammatory breast cancer is allowed.

- 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.

- 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.

- 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 must agree to use contraception 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 must agree to use effective contraception 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.

- Has adequate organ function.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Has a history of non-infectious pneumonitis that required treatment with steroids or
has current pneumonitis.

- Has breast cancer with lobular histology.

- Has bilateral invasive breast cancer.

- Has metastatic (Stage IV) breast cancer.

- Has multi-centric breast cancer (presence of more than 1 tumor in different quadrants
of the breast).

- Has any of the following clinical lymph node staging per current American Joint
Committee on Cancer (AJCC) staging criteria for breast cancer staging based on
radiological and/or clinical assessment: cN3, cN3a, cN3b, or cN3c.

- Has ER-, progesterone receptor positive breast cancer.

- Has undergone excisional biopsy of the primary tumor and/or axillary lymph nodes or
has undergone sentinel lymph node biopsy prior to study treatment.

- Has a known additional, invasive, malignancy that is progressing or required active
treatment in the last 5 years.

Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, ductal breast carcinoma in situ, or cervical carcinoma in situ that has undergone
potentially curative therapy are not excluded.

- 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.

- 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) Note: Replacement therapy (e.g. thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency)
is not considered a form of systemic treatment.

- Has a known history of active tuberculosis (Bacillus tuberculosis).

- Has an active infection requiring systemic therapy.

- 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.

- Has other significant cardiac disease, such as: 1) History of myocardial infarction,
acute coronary syndrome, or coronary angioplasty/stenting/bypass within the last 6
months; or 2) Congestive heart failure (CHF) New York Heart Association (NYHA) Class
II-IV or history of CHF NYHA Class III or IV.

- Has a known history of human immunodeficiency virus (HIV) infection.

- Has a known history of hepatitis B or known active hepatitis C virus infection.

- Has received prior treatment for breast cancer.

- Has received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1),
anti-programmed cell death-ligand 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. cytotoxic
T-lymphocyte-associated protein 4 [CTLA-4], OX 40, CD137).

- Has received a live vaccine within 30 days prior to the first dose of study treatment.

- Has severe hypersensitivity (=Grade 3) to any of the components or excipients used in
the study treatments.

- 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.

- 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Chris OBrien Lifehouse ( Site 2107) - Camperdown
Recruitment hospital [2] 0 0
Royal North Shore Hospital ( Site 2100) - Sydney
Recruitment hospital [3] 0 0
Westmead Hospital ( Site 2101) - Sydney
Recruitment hospital [4] 0 0
Frankston Hospital ( Site 2103) - Frankston
Recruitment hospital [5] 0 0
Peter MacCallum Cancer Centre ( Site 2102) - Melbourne
Recruitment hospital [6] 0 0
Mater Misericordiae Ltd Mater Cancer Care Centre ( Site 2106) - South Brisbane
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
2065 - Sydney
Recruitment postcode(s) [3] 0 0
2145 - Sydney
Recruitment postcode(s) [4] 0 0
3199 - Frankston
Recruitment postcode(s) [5] 0 0
3000 - Melbourne
Recruitment postcode(s) [6] 0 0
4101 - South Brisbane
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
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United States of America
State/province [2] 0 0
Arizona
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California
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United States of America
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Colorado
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Florida
Country [6] 0 0
United States of America
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Georgia
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United States of America
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Illinois
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United States of America
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Indiana
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United States of America
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Iowa
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United States of America
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Kentucky
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Maryland
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United States of America
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Massachusetts
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Montana
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United States of America
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Nebraska
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New Jersey
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New York
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Oklahoma
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Oregon
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Pennsylvania
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South Carolina
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Tennessee
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United States of America
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Texas
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Virginia
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United States of America
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Washington
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Belgium
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Brussels
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Belgium
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Gent
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Belgium
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Hasselt
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Belgium
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Kortrijk
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Belgium
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Leuven
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Belgium
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Liege
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Belgium
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Yvoir
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Brazil
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Goias
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Brazil
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RS
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Brazil
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Santa Catarina
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Brazil
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SC
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Brazil
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SP
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Brazil
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Sao Paulo
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Canada
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Alberta
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Canada
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Ontario
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Quebec
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Colombia
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Atlantico
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Colombia
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Cundinamarca
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Colombia
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Valle Del Cauca
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Colombia
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Bogota
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Colombia
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Medellin
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Colombia
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Monteria
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France
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Avignon
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France
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Clermont Ferrand Cedex
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Dijon
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France
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Le Mans
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France
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Lille
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France
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Metz
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France
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Montpellier
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France
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Paris
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France
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Saint-Cloud
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France
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Toulouse
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France
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Villejuif
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Germany
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Bonn
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Germany
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Dresden
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Germany
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Essen
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Germany
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Saarbruecken
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Hungary
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Pest
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Hungary
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Budapest
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Hungary
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Debrecen
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Hungary
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Miskolc
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Hungary
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Pecs
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Ireland
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Cork
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Ireland
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Dublin
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Israel
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Beer Sheva
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Israel
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Haifa
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Israel
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Jerusalem
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Israel
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Petah Tikva
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Israel
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Ramat Gan
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Israel
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Rehovot
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Israel
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Tel Aviv
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Japan
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Aichi
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Japan
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Chiba
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Japan
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Hokkaido
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Japan
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Hyogo
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Japan
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Kanagawa
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Japan
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Saitama
Country [82] 0 0
Japan
State/province [82] 0 0
Shizuoka
Country [83] 0 0
Japan
State/province [83] 0 0
Fukushima
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Japan
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Hiroshima
Country [85] 0 0
Japan
State/province [85] 0 0
Kumamoto
Country [86] 0 0
Japan
State/province [86] 0 0
Osaka
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Japan
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Tokyo
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Korea, Republic of
State/province [88] 0 0
Goyang-si
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Korea, Republic of
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Seoul
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New Zealand
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Newtown
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New Zealand
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Christchurch
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New Zealand
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Tauranga
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Poland
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Mazowieckie
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Poland
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Pomorskie
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Poland
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Slaskie
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Poland
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Bielsko-Biala
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Poland
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Bydgoszcz
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Poland
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Bytom
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Poland
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Gdansk
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Poland
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Warszawa
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Portugal
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Lisboa
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Portugal
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Porto
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Russian Federation
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Arkhangelsk
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Russian Federation
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Kazan
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Russian Federation
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Moscow
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Russian Federation
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Ryazan
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Russian Federation
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Saint Petersburg
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Russian Federation
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Tomsk
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Russian Federation
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Ufa
Country [110] 0 0
Spain
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Barcelona
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Madrid
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A Coruna
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Jaen
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Sevilla
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Spain
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Valencia
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Taiwan
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Taichung
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Tainan
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Taipei
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Taoyuan
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Ukraine
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Dnipropetrovsk Region
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Antonivka Village
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Dnipropetrovsk
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Ivano-Frankivsk
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Khmelnitskiy
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Kyiv
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Odesa
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Nottinghamshire
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Bristol
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London
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Truro

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Merck Sharp & Dohme Corp.
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The purpose of this study is to assess the efficacy and safety of pembrolizumab (MK-3475)
versus placebo in combination with neoadjuvant (pre-surgery) chemotherapy and adjuvant
(post-surgery) endocrine therapy in the treatment of adults who have high-risk early-stage
estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-)
breast cancer.

The primary study hypotheses are: 1) pembrolizumab is superior to placebo, both in
combination with the protocol-specified neoadjuvant anticancer therapy, as assessed by
pathological Complete Response (pCR) rate defined by the local pathologist, and 2)
pembrolizumab is superior to placebo (both in combination with the protocol-specified
neoadjuvant and adjuvant anticancer therapies) as assessed by Event-Free Survival (EFS) as
determined by the investigator. The study is considered to have met its primary objective if
pembrolizumab is superior to placebo with respect to either pCR (ypT0/Tis ypN0) or EFS.
Trial website
https://clinicaltrials.gov/show/NCT03725059
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme Corp.
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Toll Free Number
Address 0 0
Country 0 0
Phone 0 0
1-888-577-8839
Fax 0 0
Email 0 0
Trialsites@merck.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03725059