Safety and Efficacy Study of Pembrolizumab (MK-3475) in Combination With Chemotherapy as Neoadjuvant Treatment for Participants With Triple Negative Breast Cancer (TNBC) (MK-3475-173/KEYNOTE-173)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability and clinical activity of pembrolizumab (MK-3475) in combination with six chemotherapy regimens as neoadjuvant treatment for participants with triple negative breast cancer (TNBC).

Official Title
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A Phase 1b Study to Evaluate Safety and Clinical Activity of Pembrolizumab (MK-3475) in Combination With Chemotherapy as Neoadjuvant Treatment for Triple Negative Breast Cancer (TNBC) - (KEYNOTE 173)

Conditions
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Triple Negative Breast Neoplasms

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Nab-paclitaxel
* Drug: Anthracycline (doxorubicin)
* Drug: Cyclophosphamide
* Drug: Carboplatin
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has previously untreated, locally advanced TNBC. Is able to provide 2 core needle biopsies from the primary tumor at screening to the central laboratory and agrees to have a core needle biopsy after single dose pembrolizumab treatment if tumor biopsy is feasible as judged by the investigator. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Has adequate organ function. Females of childbearing potential must be willing to use adequate contraception for the course of the study through 12 months after the last dose of study drug for participants receiving cyclophosphamide and through 6 months after the last dose of study drug for participants who do not receive cyclophosphamide. Exclusion Criteria: Has evidence of metastatic breast cancer, concurrent bilateral invasive breast cancer, or inflammatory breast cancer. Has another malignancy within the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative surgery, or in situ cervical cancer. Has received prior chemotherapy, targeted therapy, radiation therapy, immunotherapy that targets immune checkpoints, co-stimulatory or co-inhibitory pathways for T cell receptors within the past 12 months. Is currently participating and receiving study therapy, or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study drug. Has received a live vaccine within 30 days of the first dose of study drug. Has an active autoimmune disease that has required systemic treatment in past 2 years. 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 study drug. Has a known history of Human Immunodeficiency Virus (HIV). Has known active Hepatitis B or Hepatitis C. Has evidence of current pneumonitis. Has a history of non-infectious pneumonitis requiring treatment with steroids or a history of interstitial lung disease. 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; Congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA class III or IV Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study. 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 trial treatment for participants who have received cyclophosphamide, and for six months after the last dose of study medication for participants who have not. Has a known hypersensitivity to the components of the study drug or its analogs.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: KNp / KAC<br>Participants receive pembrolizumab (K) 200 mg on Cycle 1 Day 1 followed by pembrolizumab 200 mg in Cycles 2-5 on Day 1 (once every 3 weeks; Q3W) PLUS nab-paclitaxel (KNp) starting at 125 mg/m^2 in Cycles 2-5 on Days 1, 8 and 15 (once each week; QW). This will be followed by pembrolizumab (K) 200 mg in Cycles 6-9 on Day 1 (Q3W) PLUS doxorubicin (A) 60 mg/m^2 in Cycles 6-9 on Day 1 (Q3W) PLUS cyclophosphamide (C) 600 mg/m^2 in Cycles 6-9 on Day 1 (Q3W). All treatments will be administered via intravenous (IV) infusion except for doxorubicin (A), which will be administered via IV injection. Each cycle is 21 days. | Biological: Pembrolizumab<br>* 200 mg administered Q3W as an IV infusion.<br>* Other names: KEYTRUDA®;Drug: Nab-paclitaxel<br>* 125 mg/m^2 or 100 mg/m^2 administered weekly as an IV infusion, according to allocation.<br>Drug: Anthracycline (doxorubicin)<br>* 60 mg/m^2 administered Q3W as an IV injection.<br>Drug: Cyclophosphamide<br>* 600 mg/m^2 administered Q3W as an IV infusion.<br>|
| Experimental: Cohort B: KNpCb (Regimen 1) / KAC<br>Participants first receive KNpCb Regimen 1 which consists of: pembrolizumab (K) 200 mg on Cycle 1 Day 1 PLUS nab-paclitaxel (KNp) starting at 100 mg/m^2 in Cycles 2-5 on Days 1, 8 and 15 (QW) PLUS carboplatin (Cb) starting at Area Under the Curve (AUC) 6 in Cycles 2-5 on Day 1 (Q3W). This will be followed by pembrolizumab (K) 200 mg in Cycles 6-9 on Day 1 (Q3W) PLUS doxorubicin (A) 60 mg/m^2 in Cycles 6-9 on Day 1 (Q3W) PLUS cyclophosphamide (C) 600 mg/m^2 in Cycles 6-9 on Day 1 (Q3W). All treatments will be administered via IV infusion except for doxorubicin (A), which will be administered via IV injection. Each cycle is 21 days. | Biological: Pembrolizumab<br>* 200 mg administered Q3W as an IV infusion.<br>* Other names: KEYTRUDA®;Drug: Nab-paclitaxel<br>* 125 mg/m^2 or 100 mg/m^2 administered weekly as an IV infusion, according to allocation.<br>Drug: Anthracycline (doxorubicin)<br>* 60 mg/m^2 administered Q3W as an IV injection.<br>Drug: Cyclophosphamide<br>* 600 mg/m^2 administered Q3W as an IV infusion.<br>Drug: Carboplatin<br>* AUC 6 or AUC5 administered Q3W as an IV infusion, or AUC2 administered weekly as an IV infusion, according to allocation.<br>|
| Experimental: Cohort C: KNpCb (Regimen 2) / KAC<br>Participants first receive KNpCb Regimen 2 which consists of: pembrolizumab (K) 200 mg on Cycle 1 Day 1 PLUS nab-paclitaxel (KNp) starting at 125 mg/m^2 in Cycles 2-5 on Days 1, 8 and 15 (QW) PLUS carboplatin (Cb) starting at AUC 5 in Cycles 2-5 on Day 1 (Q3W). This will be followed by pembrolizumab (K) 200 mg in Cycles 6-9 on Day 1 (Q3W) PLUS doxorubicin (A) 60 mg/m^2 in Cycles 6-9 on Day 1 (Q3W) PLUS cyclophosphamide (C) 600 mg/m^2 in Cycles 6-9 on Day 1 (Q3W). All treatments will be administered via IV infusion except for doxorubicin (A), which will be administered via IV injection. Each cycle is 21 days. | Biological: Pembrolizumab<br>* 200 mg administered Q3W as an IV infusion.<br>* Other names: KEYTRUDA®;Drug: Nab-paclitaxel<br>* 125 mg/m^2 or 100 mg/m^2 administered weekly as an IV infusion, according to allocation.<br>Drug: Anthracycline (doxorubicin)<br>* 60 mg/m^2 administered Q3W as an IV injection.<br>Drug: Cyclophosphamide<br>* 600 mg/m^2 administered Q3W as an IV infusion.<br>Drug: Carboplatin<br>* AUC 6 or AUC5 administered Q3W as an IV infusion, or AUC2 administered weekly as an IV infusion, according to allocation.<br>|
| Experimental: Cohort D: KNpCb (Regimen 3) / KAC<br>Participants first receive KNpCb Regimen 3 which consists of: pembrolizumab (K) 200 mg on Cycle 1 Day 1 PLUS nab-paclitaxel (KNp) starting at 125 mg/m^2 in Cycles 2-5 on Days 1, 8 and 15 (QW) PLUS carboplatin (Cb) starting at AUC 2 in Cycles 2-5 on Days 1, 8 and 15 (QW). This will be followed by pembrolizumab (K) 200 mg in Cycles 6-9 on Day 1 PLUS doxorubicin (A) 60 mg/m^2 in Cycles 6-9 on Day 1 (Q3W) PLUS cyclophosphamide (C) 600 mg/m^2 in Cycles 6-9 on Day 1 (Q3W) in Cycles 6-9 on Day 1 (Q3W). All treatments will be administered via IV infusion except for doxorubicin (A), which will be administered via IV injection. Each cycle is 21 days. | Biological: Pembrolizumab<br>* 200 mg administered Q3W as an IV infusion.<br>* Other names: KEYTRUDA®;Drug: Nab-paclitaxel<br>* 125 mg/m^2 or 100 mg/m^2 administered weekly as an IV infusion, according to allocation.<br>Drug: Anthracycline (doxorubicin)<br>* 60 mg/m^2 administered Q3W as an IV injection.<br>Drug: Cyclophosphamide<br>* 600 mg/m^2 administered Q3W as an IV infusion.<br>Drug: Carboplatin<br>* AUC 6 or AUC5 administered Q3W as an IV infusion, or AUC2 administered weekly as an IV infusion, according to allocation.<br>|
| Experimental: Cohort E: KTCb (Regimen 1) / KAC<br>Participants first receive KTCb Regimen 1 which consists of: pembrolizumab (K) 200 mg on Cycle 1 Day 1 PLUS paclitaxel (T) starting at 80mg/m^2 in Cycles 2-5 on Days 1, 8, and 15 (QW) PLUS carboplatin (Cb) starting at AUC 5 in Cycles 2-5 on Day 1 (Q3W). This will be followed by pembrolizumab (K) 200 mg in Cycles 6-9 on Day 1 (Q3W) PLUS doxorubicin (A) 60 mg/m^2 in Cycles 6-9 on Day 1 (Q3W) PLUS cyclophosphamide (C) 600 mg/m^2 in Cycles 6-9 on Day 1 (Q3W). All treatments will be administered via IV infusion except for doxorubicin (A), which will be administered via IV injection. Each cycle is 21 days. | Biological: Pembrolizumab<br>* 200 mg administered Q3W as an IV infusion.<br>* Other names: KEYTRUDA®;Drug: Anthracycline (doxorubicin)<br>* 60 mg/m^2 administered Q3W as an IV injection.<br>Drug: Cyclophosphamide<br>* 600 mg/m^2 administered Q3W as an IV infusion.<br>Drug: Carboplatin<br>* AUC 6 or AUC5 administered Q3W as an IV infusion, or AUC2 administered weekly as an IV infusion, according to allocation.<br>Drug: Paclitaxel<br>* 80 mg/m^2 or 70 mg/m^2 administered weekly as an IV infusion, according to allocation.<br>|
| Experimental: Cohort F: KTCb (Regimen 2) / KAC<br>Participants first receive KTCb Regimen 2 which consists of: pembrolizumab (K) 200 mg on Cycle 1 Day 1 PLUS paclitaxel (T) starting at 80mg/m^2 in Cycles 2-5 on Days 1, 8, and 15 PLUS carboplatin (Cb) starting at AUC 2 in Cycles 2-5 on Days 1, 8 and 15 (QW). This will be followed by pembrolizumab (K) 200 mg in Cycles 6-9 on Day 1 (Q3W) PLUS doxorubicin (A) 60 mg/m^2 in Cycles 6-9 on Day 1 (Q3W) PLUS cyclophosphamide (C) 600 mg/m^2 in Cycles 6-9 on Day 1 (Q3W). All treatments will be administered via IV infusion except for doxorubicin (A), which will be administered via IV injection. Each cycle is 21 days. | Biological: Pembrolizumab<br>* 200 mg administered Q3W as an IV infusion.<br>* Other names: KEYTRUDA®;Drug: Anthracycline (doxorubicin)<br>* 60 mg/m^2 administered Q3W as an IV injection.<br>Drug: Cyclophosphamide<br>* 600 mg/m^2 administered Q3W as an IV infusion.<br>Drug: Carboplatin<br>* AUC 6 or AUC5 administered Q3W as an IV infusion, or AUC2 administered weekly as an IV infusion, according to allocation.<br>Drug: Paclitaxel<br>* 80 mg/m^2 or 70 mg/m^2 administered weekly as an IV infusion, according to allocation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) Graded Using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0) | The following events, if considered to be study-treatment-related by the Investigator, were considered a DLT: Hematologic: Grade 4 neutropenia lasting ≥8 days; Febrile neutropenia Grade 3 or Grade 4; or Grade 4 thrombocytopenia requiring platelet transfusion, or Grade 3 thrombocytopenia with bleeding Non-hematologic: Grade 4 toxicity; Grade ≥3 symptomatic hepatic toxicities lasting >48 hours, or Grade ≥3 asymptomatic hepatic toxicities lasting ≥7 days; or Grade ≥3 non-hematologic, non-hepatic organ toxicity, with exceptions Other: Any treatment delays for ≥14 days due to unresolved toxicity; Grade 5 treatment-related adverse event (AE); A dose reduction of study treatment during the DLT evaluation period. | Cycle 1 Day 1 through end of Cycle 3 and Cycle 6 Day 1 through end of Cycle 7 (Up to  150 days from first dose of first combination regimen); Each cycle was 21 days. | 
| Number of Participants Who Experienced an Adverse Event (AE) | An AE was defined as any untoward medical occurrence in a participant administered study treatment and which does not necessarily have to have a causal relationship with this treatment. The number of participants who experienced an AE either prior to or after definitive surgery is presented. | Up to approximately 28 months (through Interim database cut-off date of 31-May-2018) | 
| Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | An AE was defined as any untoward medical occurrence in a participant administered study treatment and which does not necessarily have to have a causal relationship with this treatment. The number of participants who discontinued study treatment due to an AE is presented. | Up to approximately 28 months (through Interim database cut-off date of 31-May-2018) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Complete Response (pCR) Rate Using the Definition of ypT0 ypN0 (No Invasive or Noninvasive Residual in Breast or Nodes) | pCR rate (ypT0 ypN0; no invasive or noninvasive residual in breast or nodes) was defined as the rate of absence of 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 American Joint Committee on Cancer (AJCC) staging criteria assessed by local pathologist at the time of definitive surgery. The percentage of participants with a pCR using the definition of ypT0 ypN0 is presented. | Up to approximately 9 months (at the time of definitive surgery) | 
| Pathological Complete Response (pCR) Rate Using the Definition of ypT0/Tis ypN0 (No Invasive Residual in Breast or Nodes; Noninvasive Breast Residuals Allowed) | pCR rate (ypT0/Tis ypN0; no invasive residual in breast or nodes; noninvasive breast residuals allowed) was defined as the rate of absence of 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 AJCC staging criteria assessed by local pathologist at the time of definitive surgery. The percentage of participants with a pCR using the alternative definition of ypT0/Tis ypN0 is presented. | Up to approximately 9 months (at the time of definitive surgery) | 
| Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator Review: First Combination Regimen | ORR was defined as the percentage of participants who achieved a complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters [SOD] of target lesions) according to RECIST 1.1 by Investigator review. Because imaging was assessed prior to surgery, a confirmation assessment of CR or PR was not obtained. Participants with missing outcome for objective response were considered non-responders. The percentage of participants who experienced a CR or PR based on RECIST 1.1 following the first combination regimen is presented. | At the end of Cycle 5 following treatment with the first combination regimen (KNp, KNpCb, or KTCb) (Up to  4 months); Each cycle was 21 days. | 
| Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator Review: Second Combination Regimen | ORR was defined as the percentage of participants who achieved a complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters [SOD] of target lesions) according to RECIST 1.1 by Investigator review. Because imaging was assessed prior to surgery, a confirmation assessment of CR or PR was not obtained. Participants with missing outcome for objective response were considered non-responders. The percentage of participants who experienced a CR or PR based on RECIST 1.1 following the second combination regimen is presented. | After completion of the second combination regimen (KAC; Cycle 9) but prior to surgery (Up to  9 months); Each cycle was 21 days. | 
| Event-Free Survival (EFS) Rate at Month 6 | EFS was defined as the time from the first dose date of study treatment to any of the following events: progression of disease that precludes definitive surgery, disease recurrence (for participants with complete surgical resection), progression (for participants with incomplete surgical resection), or death due to any cause. Participants without documented events were censored at the date of the last disease status assessment. The Kaplan-Meier estimates of the percentage of participants who were event free at Month 6 are presented (through Final Analysis cut-off of 18-Nov-2019). | Month 6 | 
| Event-Free Survival (EFS) Rate at Month 12 | EFS was defined as the time from the first dose date of study treatment to any of the following events: progression of disease that precludes definitive surgery, disease recurrence (for participants with complete surgical resection), progression (for participants with incomplete surgical resection), or death due to any cause. Participants without documented events were censored at the date of the last disease status assessment. The Kaplan-Meier estimates of the percentage of participants who were event free at Month 12 are presented (through Final Analysis cut-off of 18-Nov-2019). | Month 12 | 
| Event-Free Survival (EFS) Rate at Month 24 | EFS was defined as the time from the first dose date of study treatment to any of the following events: progression of disease that precludes definitive surgery, disease recurrence (for participants with complete surgical resection), progression (for participants with incomplete surgical resection), or death due to any cause. Participants without documented events were censored at the date of the last disease status assessment. The Kaplan-Meier estimates of the percentage of participants who were event free at Month 24 are presented (through Final Analysis cut-off of 18-Nov-2019). | Month 24 | 
| Overall Survival (OS) Rate at Month 6 | OS was defined as the time from the first dose date of study treatment to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. The Kaplan-Meier estimates of the percentage of participants who were surviving at Month 6 are presented (through Final Analysis cut-off of 18-Nov-2019). | Month 6 | 
| Overall Survival (OS) Rate at Month 12 | OS was defined as the time from the first dose date of study treatment to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. The Kaplan-Meier estimates of the percentage of participants who were surviving at Month 12 are presented (through Final Analysis cut-off of 18-Nov-2019). | Month 12 | 
| Overall Survival (OS) Rate at Month 24 | OS was defined as the time from the first dose date of study treatment to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. The Kaplan-Meier estimates of the percentage of participants who were surviving at Month 24 are presented (through Final Analysis cut-off of 18-Nov-2019). | Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1), Triple Negative Breast Cancer