Clinical Trials List
Protocol NumberMK3475-756
NCT Number(ClinicalTrials.gov Identfier)NCT03725059
Active
2018-10-01 - 2031-09-01
Phase III
Recruiting2
Terminated3
ICD-10C50
Malignant neoplasm of breast
ICD-9174.0
Malignant neoplasm of female breast, nipple and areola
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)
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Trial Applicant
Merck Sharp & Dohme (I.A.) LLC
-
Sponsor
Merck Sharp & Dohme Corp.
-
Trial scale
Multi-Regional Multi-Center
-
Update
2026/02/01
Investigators and Locations
Co-Principal Investigator
- Zhu-Jun Loh Division of General Surgery
- 楊舜如 Division of Hematology & Oncology
- Ya-Ting Hsu Division of Hematology & Oncology
- Wei-Pang Chung Division of Hematology & Oncology
- 廖瑋安 Division of Others
- 黃建璋 Division of General Surgery
The Actual Total Number of Participants Enrolled
0 Recruiting
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Chen-Teng Wu Division of General Surgery
- Liang-Chih Liu Division of General Surgery
- 張慧雯 Division of Others
- Yao-Chung Wu Division of General Surgery
- Chih-Jung Chen Division of General Surgery
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Co-Principal Investigator
- Chi-Chang Yu Division of General Surgery
- Mengting Peng Division of Hematology & Oncology
- Yung-Chang Lin Division of Hematology & Oncology
- 周旭桓 Division of General Surgery
- 沈士哲 Division of General Surgery
- Wen-Ling Kuo Division of General Surgery
- Chan-Keng Yang Division of Hematology & Oncology
- Wen-Chi Shen Division of Hematology & Oncology
- 翁世樺 Division of Others
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Co-Principal Investigator
- 羅喬 Division of General Surgery
- 張端瑩 Division of Hematology & Oncology
- YEN-SHEN LU Division of Hematology & Oncology
- 蔡立威 Division of General Surgery
- Wei-Wu Chen Division of Hematology & Oncology
- MING-YANG WANG Division of General Surgery
- 林季宏 Division of Hematology & Oncology
- 陳怡君 Division of Hematology & Oncology
- 郭文宏 Division of General Surgery
- 林柏翰 Division of General Internal Medicine
- 李宜軒 Division of Others
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Condition/Disease
ER+/HER2- Breast Cancer
Objectives
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.
Test Drug
Keytruda
Active Ingredient
Pembrolizumab
Dosage Form
Solution for infusion
Dosage
100
Endpoints
Primary Outcome Measures :
Pathological Complete Response (pCR) Rate Using the Definition of ypT0/Tis ypN0 [ Time Frame: Up to approximately 7 months (Time of surgery) ]
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 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.
Event-Free Survival (EFS) [ Time Frame: Up to approximately 12 years ]
EFS is defined as the time from randomization to disease progression that: precludes 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.
Pathological Complete Response (pCR) Rate Using the Definition of ypT0/Tis ypN0 [ Time Frame: Up to approximately 7 months (Time of surgery) ]
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 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.
Event-Free Survival (EFS) [ Time Frame: Up to approximately 12 years ]
EFS is defined as the time from randomization to disease progression that: precludes 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.
Inclution Criteria
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria
apply:
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.
Note: Multifocal tumors defined as the presence of 2 or more foci of cancer
within the same quadrant are allowed; at least 1 of the tumors needs to be ≥2 cm.
ER+/HER2– status needs to be confirmed for each focus.
Note: Inflammatory breast cancer is allowed.
Note: Participants with node negative disease will be capped at 20% of the total
population.
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, and PD-L1 status.
Note: Adequacy of the biopsy specimen for the above analyses must be confirmed
by the central laboratory. Submission of another tumor specimen may be
required, if adequate tumor tissue was not provided the first time.
Note: Sponsor agreement is required for formalin-fixed paraffin-embedded
(FFPE) tumor tissue sample or slides that were obtained greater than 60 days
prior to the date that the informed consent was signed.
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
this 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) as defined in Appendix 3
OR
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3
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, all screening laboratory tests should be performed
within 10 days prior to initiation of study treatment.
Participants are eligible to be included in the study only if all of the following criteria
apply:
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.
Note: Multifocal tumors defined as the presence of 2 or more foci of cancer
within the same quadrant are allowed; at least 1 of the tumors needs to be ≥2 cm.
ER+/HER2– status needs to be confirmed for each focus.
Note: Inflammatory breast cancer is allowed.
Note: Participants with node negative disease will be capped at 20% of the total
population.
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, and PD-L1 status.
Note: Adequacy of the biopsy specimen for the above analyses must be confirmed
by the central laboratory. Submission of another tumor specimen may be
required, if adequate tumor tissue was not provided the first time.
Note: Sponsor agreement is required for formalin-fixed paraffin-embedded
(FFPE) tumor tissue sample or slides that were obtained greater than 60 days
prior to the date that the informed consent was signed.
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
this 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) as defined in Appendix 3
OR
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3
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, all screening laboratory tests should be performed
within 10 days prior to initiation of study treatment.
Exclusion Criteria
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
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.
Note: Participants with basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, breast ductal carcinoma in situ, or cervical carcinoma in
situ that has undergone potentially curative therapy are not excluded.
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)
Note: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency) is not considered a
form of systemic treatment.
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 trial, interfere with the participant’s involvement for
the full duration of the trial, 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 trial.
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.
Note: No HIV testing is required unless mandated by local health authority.
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.
Note: No testing for hepatitis B or hepatitis C is required unless mandated by
local health authority.
20. A WOCBP who has a positive urine pregnancy test within 72 hours before the
first dose of study treatment (see Appendix 3). 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.
Note: Seasonal influenza vaccines for injection are generally killed virus
vaccines and are allowed.
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.
Note: Participants who have entered the follow-up phase of an investigational
trial may participate as long as 4 weeks (12 months, for an investigational agent
or device with anticancer or antiproliferative properties) have elapsed since the
last dose of the previous investigational agent or last use of investigational
device.
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.
Participants are excluded from the study if any of the following criteria apply:
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.
Note: Participants with basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, breast ductal carcinoma in situ, or cervical carcinoma in
situ that has undergone potentially curative therapy are not excluded.
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)
Note: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency) is not considered a
form of systemic treatment.
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 trial, interfere with the participant’s involvement for
the full duration of the trial, 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 trial.
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.
Note: No HIV testing is required unless mandated by local health authority.
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.
Note: No testing for hepatitis B or hepatitis C is required unless mandated by
local health authority.
20. A WOCBP who has a positive urine pregnancy test within 72 hours before the
first dose of study treatment (see Appendix 3). 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.
Note: Seasonal influenza vaccines for injection are generally killed virus
vaccines and are allowed.
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.
Note: Participants who have entered the follow-up phase of an investigational
trial may participate as long as 4 weeks (12 months, for an investigational agent
or device with anticancer or antiproliferative properties) have elapsed since the
last dose of the previous investigational agent or last use of investigational
device.
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.
The Estimated Number of Participants
-
Taiwan
50 participants
-
Global
1240 participants
