Clinical Trials List
Protocol NumberMK3475-522
NCT Number(ClinicalTrials.gov Identfier)NCT03036488
2017-03-01 - 2019-12-31
Phase III
Terminated7
ICD-10C50
Malignant neoplasm of breast
A Phase III, Randomized, Double-blind Study to Evaluate Pembrolizumab Plus Chemotherapy vs Placebo Plus Chemotherapy as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant Therapy for Triple Negative Breast Cancer (TNBC)
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Trial Applicant
Merck Sharp & Dohme (I.A.) LLC
-
Sponsor
Merck Sharp & Dohme Corp.
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Trial scale
Multi-Regional Multi-Center
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Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- Zhu-Jun Loh Division of General Surgery
- Wei-Pang Chung Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Completed
The Actual Total Number of Participants Enrolled
0 Completed
Co-Principal Investigator
- 褚乃銘 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Completed
Co-Principal Investigator
- Yi-Fang Tsai Division of General Surgery
- 林燕淑 Division of General Surgery
- 金光亮 Division of General Surgery
- 邱仁輝 Division of General Surgery
- Ta-Chung Chao Division of Hematology & Oncology
- Chun-Yu Liu Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
7 Completed
Audit
None
Linkou Chang Gung Medical Foundation
Taiwan National PI
陳訓徹
Co-Principal Investigator
- Yung-Chang Lin Division of Hematology & Oncology
- Chan-Keng Yang Division of Hematology & Oncology
- Chi-Chang Yu Division of General Surgery
- Mengting Peng Division of Hematology & Oncology
- 沈士哲 Division of General Surgery
- Wen-Ling Kuo Division of General Surgery
- Wen-Chi Shen Division of Hematology & Oncology
- 周旭桓 Division of General Surgery
The Actual Total Number of Participants Enrolled
9 Completed
Audit
CRO
Co-Principal Investigator
- 郭文宏 Division of General Surgery
- 林柏翰 Division of General Internal Medicine
- YEN-SHEN LU Division of Hematology & Oncology
- 蔡立威 Division of General Surgery
- 羅喬 Division of General Surgery
- 林季宏 Division of Hematology & Oncology
- MING-YANG WANG Division of General Surgery
- 楊雅雯 Division of General Surgery
The Actual Total Number of Participants Enrolled
0 Completed
Audit
None
The Actual Total Number of Participants Enrolled
0 Completed
Condition/Disease
Triple Negative Breast Neoplasms
Objectives
PRIMARY OBJECTIVE(S) & HYPOTHESIS(ES)
(1) Objective: To evaluate the rate of pCR using the definition of ypT0/Tis ypN0
(i.e., no invasive residual in breast or nodes; noninvasive breast residuals
allowed) as assessed by the local pathologist at the time of definitive surgery in
subjects with locally advanced TNBC.
Hypothesis: Pembrolizumab is superior to placebo, in combination with
chemotherapy, as measured by the rate of pCR using the definition of ypT0/Tis
ypN0 as assessed by the local pathologist at the time of definitive surgery in
subjects with locally advanced TNBC.
(2) Objective: To evaluate the event-free survival (EFS) as assessed by
Investigator in subjects with locally advanced TNBC during the Neoadjuvant
and Adjuvant Treatment Phases.
Hypothesis: During the Neoadjuvant and Adjuvant Treatment Phases,
pembrolizumab is superior to placebo, as measured by EFS as assessed by the
Investigator, in subjects with locally advanced TNBC.
The study is considered to have met its primary objective if pembrolizumab is
superior to placebo in either pCR or EFS in subjects with locally advanced TNBC
at either an interim analysis or the final analysis.
Test Drug
Pembrolizumab (MK-3475) ；KEYTRUDA®/吉舒達®
Active Ingredient
Pembrolizumab (Humanized anti-PD-1 mAb)
Dosage Form
Injection
Dosage
100 mg/ 4 mL/
Endpoints
Efficacy Endpoints
pCR and EFS are proposed as dual-primary endpoints for KN522 following the FDA
guidance on “Pathological Complete Response in Neoadjuvant Treatment of High -Risk
Early-Stage Breast Cancer”. Patients who achieved pCR have demonstrated sustained
clinical benefit regardless of breast cancer subtypes. Recently, a l arge pooled analysis
demonstrated strong association of pCR, when defined as no tumor in both breast and lymph
nodes (ypT0 ypN0 or ypT0/is yp N0) following neoadjuvant therapy for breast cancer, with
improved long-term benefit as measured by event-free survival and overall survival
[Ref. 5.4: 03R26K] [Ref. 5.4: 046KDF].
Following the single trial model referred to in the above FDA guidance, patients entering the
study that supported accelerated approval will be followed for survival endpoints such as
EFS or OS. As such, EFS is proposed as a dual-primary efficacy endpoint with pCR.
Safety Endpoints
Safety parameters such as incidence of AE/SAEs (including fatal SAEs), immune-related
AEs (irAEs) and laboratory abnormalities, rates of dose interruption and discontinuation due
to AEs, and ECI are important endpoints for safety and tolerability evaluations.
pCR and EFS are proposed as dual-primary endpoints for KN522 following the FDA
guidance on “Pathological Complete Response in Neoadjuvant Treatment of High -Risk
Early-Stage Breast Cancer”. Patients who achieved pCR have demonstrated sustained
clinical benefit regardless of breast cancer subtypes. Recently, a l arge pooled analysis
demonstrated strong association of pCR, when defined as no tumor in both breast and lymph
nodes (ypT0 ypN0 or ypT0/is yp N0) following neoadjuvant therapy for breast cancer, with
improved long-term benefit as measured by event-free survival and overall survival
[Ref. 5.4: 03R26K] [Ref. 5.4: 046KDF].
Following the single trial model referred to in the above FDA guidance, patients entering the
study that supported accelerated approval will be followed for survival endpoints such as
EFS or OS. As such, EFS is proposed as a dual-primary efficacy endpoint with pCR.
Safety Endpoints
Safety parameters such as incidence of AE/SAEs (including fatal SAEs), immune-related
AEs (irAEs) and laboratory abnormalities, rates of dose interruption and discontinuation due
to AEs, and ECI are important endpoints for safety and tolerability evaluations.
Inclution Criteria
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written 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.
2. Be a male or female subject 18 years of age on day of signing informed
consent.
3. Have centrally confirmed TNBC, as defined by the most recent ASCO/CAP
guidelines.
4. Have previously untreated locally advanced non-metastatic (M0) TNBC
defined as the following combined primary tumor (T) and regional lymph node
(N) staging per AJCC for breast cancer staging criteria version 7 as assessed by
the investigator based on radiological and/or clinical assessment:
T1c, N1-N2
T2, N0-N2
T3, N0-N2
T4a-d, N0-N2
Note: bilateral and/or multifocal primary tumor is allowed, as well as
inflammatory breast cancer, and the tumor with the most advanced T stage
should be used to assess the eligibility. If multi-focal/multi-centric disease,
TNBC needs to be confirmed for each focus.
5. Provide a core needle biopsy consisting of at least 2 separate tumor cores from
the primary tumor at screening to the central laboratory.
6. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
1 performed within 10 days of treatment initiation.
7. Demonstrate adequate organ function as defined in Table 1. All screening labs
should be performed within 10 days of treatment initiation.
8. Have left ventricular ejection fraction (LVEF) of ≥50% or ≥ institution lower
limit of normal (LLN) as assessed by echocardiogram (ECHO) or multigated
acquisition (MUGA) scan performed at screening.
9. Males and female subjects of childbearing potential must be willing to use an
adequate method of contraception as outlined in Protocol Section 5.7.2 –
Contraception, for the course of the study through 12 months after the last dose
of study medication for subjects who have received cyclophosphamide, and 6
months after the last dose of study medication for subjects who did not.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
10. (Female subject of childbearing potential) Have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study
medication. If the urine test is positive or borderline a serum pregnancy test
will be required
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written 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.
2. Be a male or female subject 18 years of age on day of signing informed
consent.
3. Have centrally confirmed TNBC, as defined by the most recent ASCO/CAP
guidelines.
4. Have previously untreated locally advanced non-metastatic (M0) TNBC
defined as the following combined primary tumor (T) and regional lymph node
(N) staging per AJCC for breast cancer staging criteria version 7 as assessed by
the investigator based on radiological and/or clinical assessment:
T1c, N1-N2
T2, N0-N2
T3, N0-N2
T4a-d, N0-N2
Note: bilateral and/or multifocal primary tumor is allowed, as well as
inflammatory breast cancer, and the tumor with the most advanced T stage
should be used to assess the eligibility. If multi-focal/multi-centric disease,
TNBC needs to be confirmed for each focus.
5. Provide a core needle biopsy consisting of at least 2 separate tumor cores from
the primary tumor at screening to the central laboratory.
6. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
1 performed within 10 days of treatment initiation.
7. Demonstrate adequate organ function as defined in Table 1. All screening labs
should be performed within 10 days of treatment initiation.
8. Have left ventricular ejection fraction (LVEF) of ≥50% or ≥ institution lower
limit of normal (LLN) as assessed by echocardiogram (ECHO) or multigated
acquisition (MUGA) scan performed at screening.
9. Males and female subjects of childbearing potential must be willing to use an
adequate method of contraception as outlined in Protocol Section 5.7.2 –
Contraception, for the course of the study through 12 months after the last dose
of study medication for subjects who have received cyclophosphamide, and 6
months after the last dose of study medication for subjects who did not.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
10. (Female subject of childbearing potential) Have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study
medication. If the urine test is positive or borderline a serum pregnancy test
will be required
Exclusion Criteria
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has a history of invasive malignancy ≤5 years prior to signing informed
consent except for adequately treated basal cell or squamous cell skin cancer or
in situ cervical cancer.
2. Has received prior chemotherapy, targeted therapy, and radiation therapy
within the past 12 months.
3. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
or with an agent directed to another co-inhibitory T-cell receptor (e.g.,
CTLA-4, OX-40, CD137) or has previously participated in MK-3475 clinical
trials.
4. Is currently participating in or has participated in an interventional clinical trial
with an investigational compound or device within 4 weeks of the first dose of
treatment in this current trial.
Note: subject should be excluded if he/she received an investigational agent
with anti-cancer or anti-proliferative intent within the last 12 months.
5. Has received a live vaccine within 30 days of the first dose of study treatment.
Note: Seasonal influenza vaccines for injection are generally inactivated flu
vaccines and are allowed; however intranasal influenza vaccines (e.g.,
FluMist®
) are live attenuated vaccines, and are not allowed.
6. Has an active autoimmune disease that has required systemic treatment in 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) is not considered a form of systemic treatment.
7. 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.
8. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2
antibodies).
9. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV
RNA [qualitative] is detected).
10. Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis.
11. Has an active infection requiring systemic therapy.
12. Has significant cardiovascular disease, such as:
History of myocardial infarction, acute coronary syndrome or coronary
angioplasty/stenting/bypass grafting 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
13. Has a history or current evidence of any condition, therapy, lab abnormality or
other circumstance that might expose the subject to risk by participating in the
trial, confound the results of the trial, or interfere with the subject’s
participation for the full duration of the trial.
14. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
15. Is pregnant or breastfeeding, or expecting to conceive children within the
projected duration of the trial, starting with the screening visit through 12
months after the last dose of trial treatment for subjects who have received
cyclophospha mide, and for 6 months after the last dose of study medication for subjects who have not.
16. Has a known hypersensitivity to the components of the study therapy or its
analogs.
17. Has a known history of active TB (Bacillus Tuberculosis)
The subject must be excluded from participating in the trial if the subject:
1. Has a history of invasive malignancy ≤5 years prior to signing informed
consent except for adequately treated basal cell or squamous cell skin cancer or
in situ cervical cancer.
2. Has received prior chemotherapy, targeted therapy, and radiation therapy
within the past 12 months.
3. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
or with an agent directed to another co-inhibitory T-cell receptor (e.g.,
CTLA-4, OX-40, CD137) or has previously participated in MK-3475 clinical
trials.
4. Is currently participating in or has participated in an interventional clinical trial
with an investigational compound or device within 4 weeks of the first dose of
treatment in this current trial.
Note: subject should be excluded if he/she received an investigational agent
with anti-cancer or anti-proliferative intent within the last 12 months.
5. Has received a live vaccine within 30 days of the first dose of study treatment.
Note: Seasonal influenza vaccines for injection are generally inactivated flu
vaccines and are allowed; however intranasal influenza vaccines (e.g.,
FluMist®
) are live attenuated vaccines, and are not allowed.
6. Has an active autoimmune disease that has required systemic treatment in 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) is not considered a form of systemic treatment.
7. 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.
8. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2
antibodies).
9. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV
RNA [qualitative] is detected).
10. Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis.
11. Has an active infection requiring systemic therapy.
12. Has significant cardiovascular disease, such as:
History of myocardial infarction, acute coronary syndrome or coronary
angioplasty/stenting/bypass grafting 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
13. Has a history or current evidence of any condition, therapy, lab abnormality or
other circumstance that might expose the subject to risk by participating in the
trial, confound the results of the trial, or interfere with the subject’s
participation for the full duration of the trial.
14. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
15. Is pregnant or breastfeeding, or expecting to conceive children within the
projected duration of the trial, starting with the screening visit through 12
months after the last dose of trial treatment for subjects who have received
cyclophospha mide, and for 6 months after the last dose of study medication for subjects who have not.
16. Has a known hypersensitivity to the components of the study therapy or its
analogs.
17. Has a known history of active TB (Bacillus Tuberculosis)
The Estimated Number of Participants
-
Taiwan
50 participants
-
Global
855 participants
