Clinical Trials List
Protocol NumberMK3475-355
NCT Number(ClinicalTrials.gov Identfier)NCT02819518
2017-07-26 - 2020-06-30
Phase III
Terminated5
Study ended1
ICD-10C50
Malignant neoplasm of breast
A Randomized, Double-Blind, Phase III Study of Pembrolizumab (MK-3475) Plus Chemotherapy vs Placebo Plus Chemotherapy for Previously Untreated Locally Recurrent Inoperable or Metastatic Triple Negative Breast Cancer - (KEYNOTE-355)
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Trial Applicant
Merck Sharp & Dohme (I.A.) LLC
-
Sponsor
Merck Sharp & Dohme Corp.
-
Trial scale
Multi-Regional Multi-Center
-
Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- 邱仁輝 Division of General Surgery
- 金光亮 Division of General Surgery
- 林永慧 Division of Radiology
- Ta-Chung Chao Division of Hematology & Oncology
- Yi-Fang Tsai Division of General Surgery
- Chun-Yu Liu Division of Hematology & Oncology
- 林燕淑 Division of General Surgery
The Actual Total Number of Participants Enrolled
3 Terminated
Audit
None
Co-Principal Investigator
- 黃文聰 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Shau-Hsuan Li Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- 褚乃銘 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- YEN-SHEN LU Division of Hematology & Oncology
- 羅喬 Division of General Surgery
- MING-YANG WANG Division of General Surgery
- 張端瑩 Division of Hematology & Oncology
- 林柏翰 Division of General Internal Medicine
- 郭文宏 Division of General Surgery
- 林季宏 Division of Hematology & Oncology
- 蔡立威 Division of General Surgery
- Wei-Wu Chen Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Audit
None
Co-Principal Investigator
- Jui-Hung Tsai Division of Hematology & Oncology
- Wu-Chou Su Division of Hematology & Oncology
- Ya-Ting Hsu Division of Hematology & Oncology
- Ya-Ping Chen Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Study ended
Audit
None
Condition/Disease
Previously Untreated Locally Recurrent Inoperable or Metastatic Triple Negative Breast Cancer
Objectives
Part 1 (Safety Run-In):(1)Objective: To evaluate the safety and tolerability of 3 pembrolizumab +chemotherapy combinations, namely, pembrolizumab + paclitaxel,pembrolizumab + nab-paclitaxel, and pembrolizumab +gemcitabine/carboplatin.Part 2 (Phase III study):The combination of pembrolizumab and chemotherapy will be compared to placeboand chemotherapy for the treatment of previously untreated locally recurrentinoperable or metastatic centrally confirmed triple negative breast cancer (TNBC):(1)Objective: To compare progression-free survival (PFS) based on ResponseEvaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed bya blinded central imaging vendor (CIV) in all subjects.(2)Objective: To compare PFS based on RECIST 1.1 as assessed by a blindedCIV in subjects with programmed cell death ligand 1 (PD-L1) positivetumors.(3)Objective: To compare overall survival (OS) in all subjects.Hypothesis: The combination of pembrolizumab and chemotherapyprolongs OS compared to placebo and chemotherapy in all subjects.(4)Objective: To compare OS in subjects with PD-L1 positive tumors.Hypothesis: The combination of pembrolizumab and chemotherapyprolongs OS compared to placebo and chemotherapy in subjects with PD-L1positive tumors.
Test Drug
Pembrolizumab (MK-3475)
Active Ingredient
Pembrolizumab
Dosage Form
Injection
Dosage
100 mg/ 4 mL/ vial
Endpoints
Primary Outcome Measures :
Part 1: Percentage of Participants Who Experience an Adverse Event (AE) - All Participants [ Time Frame: Up to 45 months ]
Part 1: Percentage of Participants Who Discontinue Study Drug Due to an AE - All Participants [ Time Frame: Up to 45 months ]
Part 2: Progression-Free Survival (PFS) - All Participants [ Time Frame: Up to 45 months ]
Part 2: PFS - Participants with Programmed Cell Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 Tumors [ Time Frame: Up to 45 months ]
Part 2: PFS - Participants with PD-L1 CPS ≥10 Tumors [ Time Frame: Up to 45 months ]
Part 2: Overall Survival (OS) - All Participants [ Time Frame: Up to 45 months ]
Part 2: OS - Participants with PD-L1 CPS ≥1 Tumors [ Time Frame: Up to 45 months ]
Part 2: OS - Participants with PD-L1 CPS ≥10 Tumors [ Time Frame: Up to 45 months ]
Part 1: Percentage of Participants Who Experience an Adverse Event (AE) - All Participants [ Time Frame: Up to 45 months ]
Part 1: Percentage of Participants Who Discontinue Study Drug Due to an AE - All Participants [ Time Frame: Up to 45 months ]
Part 2: Progression-Free Survival (PFS) - All Participants [ Time Frame: Up to 45 months ]
Part 2: PFS - Participants with Programmed Cell Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 Tumors [ Time Frame: Up to 45 months ]
Part 2: PFS - Participants with PD-L1 CPS ≥10 Tumors [ Time Frame: Up to 45 months ]
Part 2: Overall Survival (OS) - All Participants [ Time Frame: Up to 45 months ]
Part 2: OS - Participants with PD-L1 CPS ≥1 Tumors [ Time Frame: Up to 45 months ]
Part 2: OS - Participants with PD-L1 CPS ≥10 Tumors [ Time Frame: Up to 45 months ]
Inclution Criteria
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Have signed informed consent to study participation. The subject may also
provide consent for Future Biomedical Research (FBR). However, the
subject may participate in the main trial without participating in FBR.
2. Be at least 18 years of age on the day of signing informed consent.
3. Have locally recurrent inoperable breast cancer not previously treated with
chemotherapy and which cannot be treated with curative intent.
OR
Have metastatic breast cancer not previously treated with chemotherapy.
Note: Subjects with a history of locally recurrent breast cancer, which was
previously treated with curative intent, may be eligible.
4. Have centrally confirmed TNBC, as defined by the most recent ASCO/CAP
guidelines.
Note: Subjects initially diagnosed with hormone receptor–positive and/or
HER2-positive breast cancer must have central confirmation of TNBC in a
tumor biopsy obtained from a local recurrence or distant metastasis site.
5. Have completed treatment for Stage I-III breast cancer, if indicated, and
≥6 months elapsed between the completion of treatment with curative intent
(e.g., date of primary breast tumor surgery or date of last adjuvant
chemotherapy administration, whichever occurred last) and first documented
local or distant disease recurrence.
Note: First documentation of local or distant disease recurrence must be in
the form of a dated biopsy, pathology, or imaging study report. A
laboratory report indicating tumor marker elevation cannot be used as
documentation of local or distant disease recurrence, unless accompanied by dated biopsy, pathology, or imaging study report.
Note: Subjects who received taxane, gemcitabine, or platinum agents in the
(neo)adjuvant setting can be treated with same class of chemotherapy (taxane
or gemcitabine/carboplatin), if ≥12 months have elapsed between the
completion of treatment with curative intent (e.g., date of primary breast
tumor surgery or date of last adjuvant chemotherapy administration,
whichever occurred last) and first documented local or distant disease
recurrence.
6. Have been treated with (neo)adjuvant anthracycline, if they received systemic
treatment in the (neo)adjuvant setting, unless anthracycline was
contraindicated or not considered the best treatment option for the subject in
the opinion of the treating physician.
Note: Subjects presenting with de novo metastatic TNBC are eligible for
the study, if anthracycline is contraindicated or not considered the best
treatment option for the subject in the opinion of the treating physician.
7. Have measurable disease based on RECIST 1.1 as determined by local
radiology review.
Note: Target lesions situated in a previously irradiated area are considered
measurable, only if they have shown unequivocal progression based on
RECIST 1.1 after radiation therapy.
Note: Chest wall recurrence can be used as a target lesion, only if
measurable by diagnostic quality imaging modality (digital photography
alone is not adequate).
8. Have provided recently or newly obtained core or excisional biopsy from a
locally recurrent inoperable or metastatic tumor lesion for central
determination of TNBC status and PD-L1 expression, unless contraindicated
due to site inaccessibility and/or subject safety concerns.
Note: Adequacy of 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: An archival tumor specimen obtained before the diagnosis of locally
recurrent inoperable or metastatic breast cancer may be submitted after
consultation with the Sponsor, if neither a recently nor a newly obtained
biopsy from a locally recurrent inoperable or a metastatic site is available.
9. Have an Eastern Cooperative Oncology Group (ECOG) performance status
of 0 or 1, as assessed within 10 days prior to the start of study treatment.
10. Have life expectancy ≥12 weeks from randomization.
11. Demonstrate adequate organ function, within 10 days prior to the start of
study treatment, as defined in the following table (Table ).
12. Female subjects of childbearing potential must have a negative urine or
serum pregnancy test within 72 hours prior to receiving the first dose of study
treatment. If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required.
13. Female subjects of childbearing potential must be willing to use an adequate
method of contraception as outlined in Section 5.7.2 – Contraception, for the
course of the study through 120 days (or longer as specified by local
institutional guidelines) after the last dose of study treatment.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
14. Male subjects of childbearing potential must agree to use an adequate method
of contraception as outlined in Section 5.7.2 – Contraception, starting with
the first dose of study therapy through 120 days (or longer as specified by
local institutional guidelines) after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
In order to be eligible for participation in this trial, the subject must:
1. Have signed informed consent to study participation. The subject may also
provide consent for Future Biomedical Research (FBR). However, the
subject may participate in the main trial without participating in FBR.
2. Be at least 18 years of age on the day of signing informed consent.
3. Have locally recurrent inoperable breast cancer not previously treated with
chemotherapy and which cannot be treated with curative intent.
OR
Have metastatic breast cancer not previously treated with chemotherapy.
Note: Subjects with a history of locally recurrent breast cancer, which was
previously treated with curative intent, may be eligible.
4. Have centrally confirmed TNBC, as defined by the most recent ASCO/CAP
guidelines.
Note: Subjects initially diagnosed with hormone receptor–positive and/or
HER2-positive breast cancer must have central confirmation of TNBC in a
tumor biopsy obtained from a local recurrence or distant metastasis site.
5. Have completed treatment for Stage I-III breast cancer, if indicated, and
≥6 months elapsed between the completion of treatment with curative intent
(e.g., date of primary breast tumor surgery or date of last adjuvant
chemotherapy administration, whichever occurred last) and first documented
local or distant disease recurrence.
Note: First documentation of local or distant disease recurrence must be in
the form of a dated biopsy, pathology, or imaging study report. A
laboratory report indicating tumor marker elevation cannot be used as
documentation of local or distant disease recurrence, unless accompanied by dated biopsy, pathology, or imaging study report.
Note: Subjects who received taxane, gemcitabine, or platinum agents in the
(neo)adjuvant setting can be treated with same class of chemotherapy (taxane
or gemcitabine/carboplatin), if ≥12 months have elapsed between the
completion of treatment with curative intent (e.g., date of primary breast
tumor surgery or date of last adjuvant chemotherapy administration,
whichever occurred last) and first documented local or distant disease
recurrence.
6. Have been treated with (neo)adjuvant anthracycline, if they received systemic
treatment in the (neo)adjuvant setting, unless anthracycline was
contraindicated or not considered the best treatment option for the subject in
the opinion of the treating physician.
Note: Subjects presenting with de novo metastatic TNBC are eligible for
the study, if anthracycline is contraindicated or not considered the best
treatment option for the subject in the opinion of the treating physician.
7. Have measurable disease based on RECIST 1.1 as determined by local
radiology review.
Note: Target lesions situated in a previously irradiated area are considered
measurable, only if they have shown unequivocal progression based on
RECIST 1.1 after radiation therapy.
Note: Chest wall recurrence can be used as a target lesion, only if
measurable by diagnostic quality imaging modality (digital photography
alone is not adequate).
8. Have provided recently or newly obtained core or excisional biopsy from a
locally recurrent inoperable or metastatic tumor lesion for central
determination of TNBC status and PD-L1 expression, unless contraindicated
due to site inaccessibility and/or subject safety concerns.
Note: Adequacy of 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: An archival tumor specimen obtained before the diagnosis of locally
recurrent inoperable or metastatic breast cancer may be submitted after
consultation with the Sponsor, if neither a recently nor a newly obtained
biopsy from a locally recurrent inoperable or a metastatic site is available.
9. Have an Eastern Cooperative Oncology Group (ECOG) performance status
of 0 or 1, as assessed within 10 days prior to the start of study treatment.
10. Have life expectancy ≥12 weeks from randomization.
11. Demonstrate adequate organ function, within 10 days prior to the start of
study treatment, as defined in the following table (Table ).
12. Female subjects of childbearing potential must have a negative urine or
serum pregnancy test within 72 hours prior to receiving the first dose of study
treatment. If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required.
13. Female subjects of childbearing potential must be willing to use an adequate
method of contraception as outlined in Section 5.7.2 – Contraception, for the
course of the study through 120 days (or longer as specified by local
institutional guidelines) after the last dose of study treatment.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
14. Male subjects of childbearing potential must agree to use an adequate method
of contraception as outlined in Section 5.7.2 – Contraception, starting with
the first dose of study therapy through 120 days (or longer as specified by
local institutional guidelines) after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
Exclusion Criteria
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating in a clinical study and receiving an investigational
agent and/or using an investigational device, or has participated in a clinical
study and received an investigational agent and/or used an investigational
device within 4 weeks prior to randomization.
Note: Subjects who have entered the follow-up phase of a clinical study may
participate as long as 4 weeks have elapsed since the last dose of the
investigational agent and/or removal of the device.
2. Has not recovered (e.g., to ≤Grade 1 or to baseline) from AEs due to a
previously administered therapy
Note: Alopecia of any grade is an exception to this criterion.
Note: Prior to randomization, the subject must have recovered adequately
from any toxicity and/or complications associated with any recent procedure.
3. Has neuropathy ≥Grade 2.
4. Has an active autoimmune disease that has required systemic treatment in the
past 2 years (e.g., 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.
5. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy
or any other form of immunosuppressive therapy within 7 days prior to
randomization.
6. Has a known additional malignancy that progressed or required active
treatment within the last 5 years. Exceptions include basal cell carcinoma of
the skin, squamous cell carcinoma of the skin that has undergone potentially
curative therapy, and in situ cervical cancer.
7. Has known active CNS metastases and/or carcinomatous meningitis.
Subjects with previously treated brain metastases may participate provided
they have stable brain metastases and did not receive chemotherapy for
metastatic breast cancer.
Note: Known brain metastases are considered active, if any of the following
criteria are applicable:
a. Brain imaging during screening demonstrates progression of existing
metastases and/or appearance of new lesions compared to brain
imaging performed at least 4 weeks earlier.
Radiographic stability of previously treated brain metastases is
based on local radiology/investigator review, but dated reports of
2 imaging studies (the most recent performed during screening)
documenting stability of brain metastasis(es) over ≥4 weeks must
be submitted to the Sponsor. Such brain imaging studies should
be available at the site for submission to CIV, if later needed.
b. Neurological symptoms attributed to brain metastases have not
returned to baseline
c. Steroids were used for management of symptoms related to brain
metastases within 28 days of randomization
8. Has active, or a history of, pneumonitis requiring treatment with steroids.
9. Has active, or a history of, interstitial lung disease.
10. Has a known history of active TB (Bacillus Tuberculosis)
11. Has an active infection requiring systemic therapy.
12. Has a history of class II-IV congestive heart failure or myocardial infarction
within 6 months of randomization.
13. Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the study, interfere with
subject participation for the full duration of the study, or render study
participation not compatible with the subject’s best interest, in the opinion of
the treating Investigator.
14. Has a known psychiatric or substance abuse disorders that would interfere
with cooperation with the requirements of the study.
15. Is pregnant or breastfeeding, or expecting to conceive or father children
within the projected duration of the study, starting with the screening visit
through 120 days (or longer as specified by local institutional guidelines)
after the last dose of study treatment.
16. 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 (such
as CTLA-4, OX-40, CD137) or has previously participated in Merck
pembrolizumab (MK-3475) clinical studies.
17. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2
antibodies).
18. Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg]
reactive) or hepatitis C (e.g., HCV RNA [qualitative] is detected).
19. Has received a live vaccine within 30 days prior to randomization.
20. Has a known history of hypersensitivity or allergy to pembrolizumab and any
of its components and/or to any of the study chemotherapies (e.g.,
nab-paclitaxel, paclitaxel, gemcitabine, or carboplatin) and any of their
components.
21. Is receiving any medication prohibited in combination with study
chemotherapies as described in the respective product labels, unless
medication was stopped within 7 days prior to randomization.
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating in a clinical study and receiving an investigational
agent and/or using an investigational device, or has participated in a clinical
study and received an investigational agent and/or used an investigational
device within 4 weeks prior to randomization.
Note: Subjects who have entered the follow-up phase of a clinical study may
participate as long as 4 weeks have elapsed since the last dose of the
investigational agent and/or removal of the device.
2. Has not recovered (e.g., to ≤Grade 1 or to baseline) from AEs due to a
previously administered therapy
Note: Alopecia of any grade is an exception to this criterion.
Note: Prior to randomization, the subject must have recovered adequately
from any toxicity and/or complications associated with any recent procedure.
3. Has neuropathy ≥Grade 2.
4. Has an active autoimmune disease that has required systemic treatment in the
past 2 years (e.g., 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.
5. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy
or any other form of immunosuppressive therapy within 7 days prior to
randomization.
6. Has a known additional malignancy that progressed or required active
treatment within the last 5 years. Exceptions include basal cell carcinoma of
the skin, squamous cell carcinoma of the skin that has undergone potentially
curative therapy, and in situ cervical cancer.
7. Has known active CNS metastases and/or carcinomatous meningitis.
Subjects with previously treated brain metastases may participate provided
they have stable brain metastases and did not receive chemotherapy for
metastatic breast cancer.
Note: Known brain metastases are considered active, if any of the following
criteria are applicable:
a. Brain imaging during screening demonstrates progression of existing
metastases and/or appearance of new lesions compared to brain
imaging performed at least 4 weeks earlier.
Radiographic stability of previously treated brain metastases is
based on local radiology/investigator review, but dated reports of
2 imaging studies (the most recent performed during screening)
documenting stability of brain metastasis(es) over ≥4 weeks must
be submitted to the Sponsor. Such brain imaging studies should
be available at the site for submission to CIV, if later needed.
b. Neurological symptoms attributed to brain metastases have not
returned to baseline
c. Steroids were used for management of symptoms related to brain
metastases within 28 days of randomization
8. Has active, or a history of, pneumonitis requiring treatment with steroids.
9. Has active, or a history of, interstitial lung disease.
10. Has a known history of active TB (Bacillus Tuberculosis)
11. Has an active infection requiring systemic therapy.
12. Has a history of class II-IV congestive heart failure or myocardial infarction
within 6 months of randomization.
13. Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the study, interfere with
subject participation for the full duration of the study, or render study
participation not compatible with the subject’s best interest, in the opinion of
the treating Investigator.
14. Has a known psychiatric or substance abuse disorders that would interfere
with cooperation with the requirements of the study.
15. Is pregnant or breastfeeding, or expecting to conceive or father children
within the projected duration of the study, starting with the screening visit
through 120 days (or longer as specified by local institutional guidelines)
after the last dose of study treatment.
16. 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 (such
as CTLA-4, OX-40, CD137) or has previously participated in Merck
pembrolizumab (MK-3475) clinical studies.
17. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2
antibodies).
18. Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg]
reactive) or hepatitis C (e.g., HCV RNA [qualitative] is detected).
19. Has received a live vaccine within 30 days prior to randomization.
20. Has a known history of hypersensitivity or allergy to pembrolizumab and any
of its components and/or to any of the study chemotherapies (e.g.,
nab-paclitaxel, paclitaxel, gemcitabine, or carboplatin) and any of their
components.
21. Is receiving any medication prohibited in combination with study
chemotherapies as described in the respective product labels, unless
medication was stopped within 7 days prior to randomization.
The Estimated Number of Participants
-
Taiwan
20 participants
-
Global
858 participants
