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)

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Triple Negative Breast Neoplasms

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: Doxorubicin
* Drug: Epirubicin
* Drug: Cyclophosphamide
* Drug: Placebo
* Biological: Granulocyte colony stimulating factor: Filgrastim or Pegfilgastrim


Participation Criteria
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Eligibility Criteria
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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. 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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab + Chemotherapy<br>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. | Biological: Pembrolizumab<br>* On Day 1 of each cycle in the neoadjuvant and adjuvant phases of the study for a total of 17 cycles; intravenous (IV) infusion.<br>* Other names: KEYTRUDA®;Drug: Carboplatin<br>* 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.<br>* Other names: PARAPLATIN®;Drug: Paclitaxel<br>* On Days 1, 8 and 15 of Cycles 1-4 in the neoadjuvant phase of the study; IV infusion.<br>* Other names: TAXOL®;Drug: Doxorubicin<br>* On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV injection.<br>* Other names: ADRIAMYCIN®;Drug: Epirubicin<br>* On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV injection.<br>* Other names: ELLENCE®;Drug: Cyclophosphamide<br>* On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV infusion.<br>* Other names: CYTOXAN®;Biological: Granulocyte colony stimulating factor: Filgrastim or Pegfilgastrim<br>* 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.<br>* Other names: NEULASTA®;|
| Active Comparator: Placebo + Chemotherapy<br>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. | Drug: Carboplatin<br>* 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.<br>* Other names: PARAPLATIN®;Drug: Paclitaxel<br>* On Days 1, 8 and 15 of Cycles 1-4 in the neoadjuvant phase of the study; IV infusion.<br>* Other names: TAXOL®;Drug: Doxorubicin<br>* On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV injection.<br>* Other names: ADRIAMYCIN®;Drug: Epirubicin<br>* On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV injection.<br>* Other names: ELLENCE®;Drug: Cyclophosphamide<br>* On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV infusion.<br>* Other names: CYTOXAN®;Drug: Placebo<br>* 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<br>Biological: Granulocyte colony stimulating factor: Filgrastim or Pegfilgastrim<br>* 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.<br>* Other names: NEULASTA®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 current American Joint Committee on Cancer (AJCC) staging criteria assessed by the local pathologist at the time of definitive surgery. | Up to approximately 27-30 weeks | 
| Event-free Survival (EFS) as assessed by Investigator | EFS is defined as the time from randomization to any of the following events: progression of disease that precludes surgery, local or distant recurrence, second primary malignancy (breast or other cancers) or death due to any cause. | Up to approximately 8 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | pCR rate (ypT0 ypN0) is defined as the percentage of participants without residual invasive and in situ 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 current AJCC staging criteria assessed by the local pathologist at the time of definitive surgery in all participants and in participants with tumors expressing Programmed Death-Ligand 1 (PD-L1). | Up to approximately 27-30 weeks | 
| 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 | pCR rate (ypT0/Tis) is defined as the percentage of participants without invasive cancer in the breast irrespective of ductal carcinoma in situ or nodal involvement following completion of neoadjuvant systemic therapy by current AJCC staging criteria assessed by the local pathologist at the time of definitive surgery in participants with tumors expressing PD-L1. | Up to approximately 27-30 weeks | 
| EFS in participants with tumors expressing PD-L1 | EFS is defined as the time from randomization to any of the following events: progression of disease that precludes surgery, local or distant recurrence, second primary malignancy (breast or other cancers) or death due to any cause. | Up to approximately 8 years | 
| 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 | pCR rate (ypT0/Tis) is defined as the percentage of participants without invasive cancer in the breast irrespective of ductal carcinoma in situ or nodal involvement following completion of neoadjuvant systemic therapy by current AJCC staging criteria assessed by the local pathologist at the time of definitive surgery in all participants and in participants with tumors expressing PD-L1. | Up to approximately 27-30 weeks | 
| Overall survival (OS) | OS is defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis will be censored at the date of the last follow-up. | Up to approximately 8 years | 
| Percentage of participants who experience an adverse event (AE) | An AE is defined as any untoward medical occurrence in a participant administered study treatment which does not necessarily have to have a causal relationship with this treatment. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment or protocol-specified procedure, whether or not considered related to study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE. | Up to approximately 61 weeks | 
| Percentage of participants who discontinue study treatment due to an AE | An AE is defined as any untoward medical occurrence in a participant administered study treatment which does not necessarily have to have a causal relationship with this treatment. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment or protocol-specified procedure, whether or not considered related to study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE. | Up to approximately 57 weeks | 
| European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 Questionnaire (QLQ-C30) score | The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Individual responses are given on a 4-point scale (1=Not at All to 4=Very Much), with a lower score indicating a better outcome. The EORTC-QLQ-C30 score will be presented for all participants and for participants with tumors expressing PD-L1. | Up to approximately 27-30 weeks | 
| 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 of breast cancer patients. Individual responses are given on a 4-point scale (1=Not at All to 4=Very Much), with a lower score indicating a better outcome. The EORTC-QLQ-BR23 score will be presented for all participants and for participants with tumors expressing PD-L1. | Up to approximately 27-30 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PD1, PD-1, PDL1, PD-L1