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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT03036488




Registration number
NCT03036488
Ethics application status
Date submitted
27/01/2017
Date registered
30/01/2017
Date last updated
3/07/2023

Titles & IDs
Public title
Study of Pembrolizumab (MK-3475) Plus Chemotherapy vs Placebo Plus Chemotherapy as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant Therapy in Participants With Triple Negative Breast Cancer (TNBC) (MK-3475-522/KEYNOTE-522)
Scientific title
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)
Secondary ID [1] 0 0
173567
Secondary ID [2] 0 0
3475-522
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Triple Negative Breast Neoplasms 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
Treatment: Drugs - Carboplatin
Treatment: Drugs - Paclitaxel
Treatment: Drugs - Doxorubicin
Treatment: Drugs - Epirubicin
Treatment: Drugs - Cyclophosphamide
Treatment: Drugs - Placebo
Other interventions - Granulocyte colony stimulating factor: Filgrastim or Pegfilgastrim

Experimental: Pembrolizumab + Chemotherapy - Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Each cycle is 21 days.

Active Comparator: Placebo + Chemotherapy - Participants receive placebo (normal saline solution) Q3W + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by placebo + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of placebo Q3W as adjuvant therapy post-surgery. Each cycle is 21 days.


Other interventions: Pembrolizumab
On Day 1 of each cycle in the neoadjuvant and adjuvant phases of the study for a total of 17 cycles; intravenous (IV) infusion.

Treatment: Drugs: Carboplatin
On Day 1 of Cycles 1-4 of the neoadjuvant phase of the study OR on Days 1, 8, 15 of Cycles 1-4 of the neoadjuvant phase of the study; IV infusion.

Treatment: Drugs: Paclitaxel
On Days 1, 8 and 15 of Cycles 1-4 in the neoadjuvant phase of the study; IV infusion.

Treatment: Drugs: Doxorubicin
On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV injection.

Treatment: Drugs: Epirubicin
On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV injection.

Treatment: Drugs: Cyclophosphamide
On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV infusion.

Treatment: Drugs: Placebo
normal saline solution or dextrose: On Day 1 of each cycle in the neoadjuvant and adjuvant phases of the study for a total of 17 cycles; IV infusion

Other interventions: Granulocyte colony stimulating factor: Filgrastim or Pegfilgastrim
For prevention of neutropenia, filgrastim 5 µg/kg/day via subcutaneous (SC) injection administered per standard of care after chemotherapy OR pegfilgastrim 100 µg/kg (individualized) or 6 mg (general approach) via SC injection administered per standard of care.
Intervention code [1] 0 0
Other interventions
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Pathological complete response (pCR) rate using the definition of ypT0/Tis ypN0 (i.e., no invasive residual in breast or nodes; noninvasive breast residuals allowed) at the time of definitive surgery
Timepoint [1] 0 0
Up to approximately 27-30 weeks
Primary outcome [2] 0 0
Event-free Survival (EFS) as assessed by Investigator
Timepoint [2] 0 0
Up to approximately 8 years
Secondary outcome [1] 0 0
pCR rate using an alternative definition, ypT0 ypN0 (i.e., no invasive or noninvasive residual in breast or nodes) at the time of definitive surgery
Timepoint [1] 0 0
Up to approximately 27-30 weeks
Secondary outcome [2] 0 0
pCR rate using the definition of ypT0/Tis ypN0 (i.e., no invasive residual in breast or nodes; noninvasive breast residuals allowed) at the time of definitive surgery
Timepoint [2] 0 0
Up to approximately 27-30 weeks
Secondary outcome [3] 0 0
EFS in participants with tumors expressing PD-L1
Timepoint [3] 0 0
Up to approximately 8 years
Secondary outcome [4] 0 0
pCR rate using an alternative definition, ypT0/Tis (i.e., absence of invasive cancer in the breast irrespective of ductal carcinoma in situ or nodal involvement) at the time of definitive surgery
Timepoint [4] 0 0
Up to approximately 27-30 weeks
Secondary outcome [5] 0 0
Overall survival (OS)
Timepoint [5] 0 0
Up to approximately 8 years
Secondary outcome [6] 0 0
Percentage of participants who experience an adverse event (AE)
Timepoint [6] 0 0
Up to approximately 61 weeks
Secondary outcome [7] 0 0
Percentage of participants who discontinue study treatment due to an AE
Timepoint [7] 0 0
Up to approximately 57 weeks
Secondary outcome [8] 0 0
European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 Questionnaire (QLQ-C30) score
Timepoint [8] 0 0
Up to approximately 27-30 weeks
Secondary outcome [9] 0 0
EORTC Breast Cancer-Specific QoL Questionnaire (QLQ-BR23) score
Timepoint [9] 0 0
Up to approximately 27-30 weeks

Eligibility
Key inclusion criteria
- Has newly diagnosed, locally advanced, centrally confirmed TNBC, as defined by the
most recent American Society of Clinical Oncology (ASCO)/College of American
Pathologists (CAP) guidelines.

- Has previously untreated locally advanced non-metastatic (M0) TNBC defined as the
following combined primary tumor (T) and regional lymph node (N) staging per current
American Joint Committee of Cancer (AJCC) staging criteria for breast cancer 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

- Provides a core needle biopsy consisting of at least 2 separate tumor cores from the
primary tumor at screening to the central laboratory.

- Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed
within 10 days of treatment initiation.

- Demonstrates adequate organ function.

- Males and female participants of childbearing potential must be willing to use an
adequate method of contraception for the course of the study through 12 months after
the last dose of study treatment for participants who have received cyclophosphamide,
and 6 months after the last dose of study treatment for participants who did not.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- 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.

- Has received prior chemotherapy, targeted therapy, and radiation therapy within the
past 12 months.

- Has received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1),
anti-programmed death - ligand 1 (anti-PD-L1), or anti-PD-L2 agent or with an agent
directed to another co-inhibitory T-cell receptor (e.g., cytotoxic
T-lymphocyte-associated antigen-4 [CTLA-4], OX-40, CD137 [tumor necrosis factor
receptor superfamily member 9 (TNFRSF9)]) or has previously participated in a
pembrolizumab (MK-3475) clinical study.

- Is currently participating in or has participated in an interventional clinical study
with an investigational compound or device within 4 weeks of the first dose of
treatment in this current study.

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

- 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).

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (i.e.,
dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study treatment.

- Has a known history of Human Immunodeficiency Virus (HIV).

- Has known active Hepatitis B or Hepatitis C.

- Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis.

- Has an active infection requiring systemic therapy.

- Has significant cardiovascular disease, such as: history of myocardial infarction,
acute coronary syndrome or coronary angioplasty/stenting/bypass grafting within the
last 6 months OR congestive heart failure (CHF) New York Heart Association (NYHA)
Class II-IV or history of CHF NYHA Class III or IV.

- Is pregnant or breastfeeding, or expecting to conceive children within the projected
duration of the study, starting with the screening visit through 12 months after the
last dose of study treatment for participants who have received cyclophosphamide, and
for 6 months after the last dose of study treatment for participants who have not.

- Has a known hypersensitivity to the components of the study treatment or its analogs.

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

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 administering 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
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
7/03/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/09/2025
Actual
Sample size
Target
Accrual to date
Final
1174
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
Recruitment hospital [1] 0 0
Royal North Shore Hospital ( Site 2000) - Sydney
Recruitment hospital [2] 0 0
Westmead Hospital ( Site 2002) - Sydney
Recruitment hospital [3] 0 0
Royal Adelaide Hospital ( Site 2008) - Adelaide
Recruitment hospital [4] 0 0
Cabrini Health ( Site 2009) - East Malvern
Recruitment hospital [5] 0 0
Frankston Hospital ( Site 2010) - Franskton
Recruitment hospital [6] 0 0
Royal Brisbane and Women s Hospital ( Site 2003) - Herston
Recruitment hospital [7] 0 0
St John of God Subiaco Hospital ( Site 2006) - Perth
Recruitment postcode(s) [1] 0 0
2065 - Sydney
Recruitment postcode(s) [2] 0 0
2145 - Sydney
Recruitment postcode(s) [3] 0 0
5000 - Adelaide
Recruitment postcode(s) [4] 0 0
3145 - East Malvern
Recruitment postcode(s) [5] 0 0
3199 - Franskton
Recruitment postcode(s) [6] 0 0
4029 - Herston
Recruitment postcode(s) [7] 0 0
6008 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Colorado
Country [4] 0 0
United States of America
State/province [4] 0 0
Connecticut
Country [5] 0 0
United States of America
State/province [5] 0 0
Delaware
Country [6] 0 0
United States of America
State/province [6] 0 0
Florida
Country [7] 0 0
United States of America
State/province [7] 0 0
Illinois
Country [8] 0 0
United States of America
State/province [8] 0 0
Indiana
Country [9] 0 0
United States of America
State/province [9] 0 0
Iowa
Country [10] 0 0
United States of America
State/province [10] 0 0
Maine
Country [11] 0 0
United States of America
State/province [11] 0 0
Michigan
Country [12] 0 0
United States of America
State/province [12] 0 0
Minnesota
Country [13] 0 0
United States of America
State/province [13] 0 0
New Jersey
Country [14] 0 0
United States of America
State/province [14] 0 0
New York
Country [15] 0 0
United States of America
State/province [15] 0 0
Ohio
Country [16] 0 0
United States of America
State/province [16] 0 0
Oregon
Country [17] 0 0
United States of America
State/province [17] 0 0
Pennsylvania
Country [18] 0 0
United States of America
State/province [18] 0 0
Rhode Island
Country [19] 0 0
United States of America
State/province [19] 0 0
Tennessee
Country [20] 0 0
United States of America
State/province [20] 0 0
Texas
Country [21] 0 0
United States of America
State/province [21] 0 0
Virginia
Country [22] 0 0
United States of America
State/province [22] 0 0
Washington
Country [23] 0 0
Brazil
State/province [23] 0 0
Rio Grande Do Sul
Country [24] 0 0
Brazil
State/province [24] 0 0
Cascavel
Country [25] 0 0
Brazil
State/province [25] 0 0
Caxias do Sul
Country [26] 0 0
Brazil
State/province [26] 0 0
Curitiba
Country [27] 0 0
Brazil
State/province [27] 0 0
Fortaleza
Country [28] 0 0
Brazil
State/province [28] 0 0
Goiania
Country [29] 0 0
Brazil
State/province [29] 0 0
Porto Alegre
Country [30] 0 0
Brazil
State/province [30] 0 0
Sao Jose do Rio Preto
Country [31] 0 0
Brazil
State/province [31] 0 0
Sao Paulo
Country [32] 0 0
Canada
State/province [32] 0 0
Alberta
Country [33] 0 0
Canada
State/province [33] 0 0
Ontario
Country [34] 0 0
Canada
State/province [34] 0 0
Quebec
Country [35] 0 0
Colombia
State/province [35] 0 0
Cordoba
Country [36] 0 0
Colombia
State/province [36] 0 0
Risaralda
Country [37] 0 0
Colombia
State/province [37] 0 0
Bogota
Country [38] 0 0
Colombia
State/province [38] 0 0
Cali
Country [39] 0 0
Colombia
State/province [39] 0 0
Medellin
Country [40] 0 0
France
State/province [40] 0 0
Besancon
Country [41] 0 0
France
State/province [41] 0 0
Bordeaux
Country [42] 0 0
France
State/province [42] 0 0
Caen
Country [43] 0 0
France
State/province [43] 0 0
Clermont-Ferrand Cedex 01
Country [44] 0 0
France
State/province [44] 0 0
Le Mans
Country [45] 0 0
France
State/province [45] 0 0
Nantes
Country [46] 0 0
France
State/province [46] 0 0
Paris
Country [47] 0 0
France
State/province [47] 0 0
Poitiers
Country [48] 0 0
France
State/province [48] 0 0
Toulouse Cedex 9
Country [49] 0 0
Germany
State/province [49] 0 0
Berlin
Country [50] 0 0
Germany
State/province [50] 0 0
Bonn
Country [51] 0 0
Germany
State/province [51] 0 0
Erlangen
Country [52] 0 0
Germany
State/province [52] 0 0
Essen
Country [53] 0 0
Germany
State/province [53] 0 0
Halle
Country [54] 0 0
Germany
State/province [54] 0 0
Hamburg
Country [55] 0 0
Germany
State/province [55] 0 0
Muenchen
Country [56] 0 0
Germany
State/province [56] 0 0
Saarbruecken
Country [57] 0 0
Germany
State/province [57] 0 0
Tubingen
Country [58] 0 0
Ireland
State/province [58] 0 0
Cork
Country [59] 0 0
Ireland
State/province [59] 0 0
Dublin
Country [60] 0 0
Israel
State/province [60] 0 0
Beer Sheva
Country [61] 0 0
Israel
State/province [61] 0 0
Beer Yaakov-Zerifin
Country [62] 0 0
Israel
State/province [62] 0 0
Jerusalem
Country [63] 0 0
Israel
State/province [63] 0 0
Petah Tikva
Country [64] 0 0
Israel
State/province [64] 0 0
Ramat-Gan
Country [65] 0 0
Israel
State/province [65] 0 0
Tel Aviv
Country [66] 0 0
Italy
State/province [66] 0 0
FC
Country [67] 0 0
Italy
State/province [67] 0 0
Brescia
Country [68] 0 0
Italy
State/province [68] 0 0
Lucca
Country [69] 0 0
Italy
State/province [69] 0 0
Macerata
Country [70] 0 0
Italy
State/province [70] 0 0
Milano
Country [71] 0 0
Italy
State/province [71] 0 0
Napoli
Country [72] 0 0
Japan
State/province [72] 0 0
Aichi
Country [73] 0 0
Japan
State/province [73] 0 0
Chiba
Country [74] 0 0
Japan
State/province [74] 0 0
Hokkaido
Country [75] 0 0
Japan
State/province [75] 0 0
Hyogo
Country [76] 0 0
Japan
State/province [76] 0 0
Kanagawa
Country [77] 0 0
Japan
State/province [77] 0 0
Osaka
Country [78] 0 0
Japan
State/province [78] 0 0
Saitama
Country [79] 0 0
Japan
State/province [79] 0 0
Shizuoka
Country [80] 0 0
Japan
State/province [80] 0 0
Hiroshima
Country [81] 0 0
Japan
State/province [81] 0 0
Kagoshima
Country [82] 0 0
Japan
State/province [82] 0 0
Kumamoto
Country [83] 0 0
Japan
State/province [83] 0 0
Tokyo
Country [84] 0 0
Korea, Republic of
State/province [84] 0 0
Seoul
Country [85] 0 0
Poland
State/province [85] 0 0
Mazowieckie
Country [86] 0 0
Poland
State/province [86] 0 0
Slaskie
Country [87] 0 0
Poland
State/province [87] 0 0
Bydgoszcz
Country [88] 0 0
Poland
State/province [88] 0 0
Gdynia
Country [89] 0 0
Poland
State/province [89] 0 0
Krakow
Country [90] 0 0
Poland
State/province [90] 0 0
Lublin
Country [91] 0 0
Poland
State/province [91] 0 0
Wroclaw
Country [92] 0 0
Portugal
State/province [92] 0 0
Lisboa
Country [93] 0 0
Portugal
State/province [93] 0 0
Porto
Country [94] 0 0
Russian Federation
State/province [94] 0 0
Arkhangelsk
Country [95] 0 0
Russian Federation
State/province [95] 0 0
Chelyabinsk
Country [96] 0 0
Russian Federation
State/province [96] 0 0
Kazan
Country [97] 0 0
Russian Federation
State/province [97] 0 0
Moscow
Country [98] 0 0
Russian Federation
State/province [98] 0 0
Ryazan
Country [99] 0 0
Russian Federation
State/province [99] 0 0
Saint Petersburg
Country [100] 0 0
Russian Federation
State/province [100] 0 0
Ufa
Country [101] 0 0
Singapore
State/province [101] 0 0
Singapore
Country [102] 0 0
Spain
State/province [102] 0 0
Barcelona
Country [103] 0 0
Spain
State/province [103] 0 0
Madrid
Country [104] 0 0
Spain
State/province [104] 0 0
Cordoba
Country [105] 0 0
Spain
State/province [105] 0 0
Santiago de Compostela
Country [106] 0 0
Spain
State/province [106] 0 0
Sevilla
Country [107] 0 0
Spain
State/province [107] 0 0
Valencia
Country [108] 0 0
Sweden
State/province [108] 0 0
Linkoping
Country [109] 0 0
Sweden
State/province [109] 0 0
Solna
Country [110] 0 0
Sweden
State/province [110] 0 0
Umea
Country [111] 0 0
Sweden
State/province [111] 0 0
Uppsala
Country [112] 0 0
Taiwan
State/province [112] 0 0
Beitou
Country [113] 0 0
Taiwan
State/province [113] 0 0
Tainan
Country [114] 0 0
Taiwan
State/province [114] 0 0
Taipei
Country [115] 0 0
Taiwan
State/province [115] 0 0
Taoyuan
Country [116] 0 0
Turkey
State/province [116] 0 0
Atakum
Country [117] 0 0
Turkey
State/province [117] 0 0
Adana
Country [118] 0 0
Turkey
State/province [118] 0 0
Ankara
Country [119] 0 0
Turkey
State/province [119] 0 0
Antalya
Country [120] 0 0
Turkey
State/province [120] 0 0
Edirne
Country [121] 0 0
Turkey
State/province [121] 0 0
Istambul
Country [122] 0 0
Turkey
State/province [122] 0 0
Istanbul
Country [123] 0 0
Turkey
State/province [123] 0 0
Izmir
Country [124] 0 0
United Kingdom
State/province [124] 0 0
Essex
Country [125] 0 0
United Kingdom
State/province [125] 0 0
London
Country [126] 0 0
United Kingdom
State/province [126] 0 0
Maidstone
Country [127] 0 0
United Kingdom
State/province [127] 0 0
Middlesbrough
Country [128] 0 0
United Kingdom
State/province [128] 0 0
Nottingham
Country [129] 0 0
United Kingdom
State/province [129] 0 0
Truro

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

Ethics approval
Ethics application status

Summary
Brief summary
The purpose of this study is to evaluate the efficacy and safety of pembrolizumab (MK-3475)
plus chemotherapy vs placebo plus chemotherapy as neoadjuvant therapy and pembrolizumab vs
placebo as adjuvant therapy in participants who have triple negative breast cancer (TNBC).

After a screening phase of approximately 28 days, each participant will receive neoadjuvant
study treatment (Pembrolizumab + Chemotherapy OR Placebo + Chemotherapy) based on the
randomization schedule for approximately 24 weeks (8 cycles). Each participant will then
undergo definitive surgery 3-6 weeks after conclusion of the last cycle of the neoadjuvant
study treatment. After definitive surgery, each participant will receive adjuvant study
treatment (Pembrolizumab OR Placebo) for approximately 27 weeks (9 cycles). Following
adjuvant study treatment, each participant will be monitored for safety, survival and disease
recurrence.

The primary study hypothesis is that pembrolizumab is superior to placebo, in combination
with chemotherapy, as measured by the rate of Pathological Complete Response (pCR) and/or
Event-free Survival (EFS), in participants with locally advanced TNBC.
Trial website
https://clinicaltrials.gov/ct2/show/NCT03036488
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme LLC
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT03036488