We are updating the design of this site. Learn more.
Show more
ClinicalTrials.gov
ClinicalTrials.gov Menu

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)

This study is currently recruiting participants.
Verified November 2017 by Merck Sharp & Dohme Corp.
Sponsor:
ClinicalTrials.gov Identifier:
NCT03036488
First Posted: January 30, 2017
Last Update Posted: November 16, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
  Purpose

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.


Condition Intervention Phase
Triple Negative Breast Neoplasms Biological: Pembrolizumab Drug: Carboplatin Drug: Paclitaxel Drug: Doxorubicin Drug: Epirubicin Drug: Cyclophosphamide Drug: Placebo Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official 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)

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • 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 [ Time Frame: Up to approximately 27-30 weeks ]
    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 American Joint Committee on Cancer (AJCC) staging criteria (7th edition) assessed by the local pathologist at the time of definitive surgery.

  • Event-free Survival (EFS) as assessed by Investigator [ Time Frame: Up to approximately 8 years ]
    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.


Secondary Outcome Measures:
  • 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 [ Time Frame: Up to approximately 27-30 weeks ]
    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 AJCC staging criteria (7th edition) assessed by the local pathologist at the time of definitive surgery.

  • 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 in participants with tumors expressing programmed cell death - ligand 1 (PD-L1) [ Time Frame: Up to approximately 27-30 weeks ]
    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 AJCC staging criteria (7th edition) assessed by the local pathologist at the time of definitive surgery.

  • EFS in participants with tumors expressing PD-L1 [ Time Frame: Up to approximately 8 years ]
    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.

  • 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 in participants with tumors expressing PD-L1 [ Time Frame: Up to approximately 27-30 weeks ]
    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 AJCC staging criteria (7th edition) assessed by the local pathologist at the time of definitive surgery.

  • 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 [ Time Frame: Up to approximately 27-30 weeks ]
    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 AJCC staging criteria (7th edition) assessed by the local pathologist at the time of definitive surgery.

  • Overall survival (OS) [ Time Frame: Up to approximately 8 years ]
    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.

  • Percentage of participants who experience an adverse event (AE) [ Time Frame: Up to approximately 61 weeks ]
    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.

  • Percentage of participants who discontinue study treatment due to an AE [ Time Frame: Up to approximately 57 weeks ]
    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.


Estimated Enrollment: 855
Actual Study Start Date: March 7, 2017
Estimated Study Completion Date: March 14, 2025
Estimated Primary Completion Date: November 1, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Biological: 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.
Other Names:
  • MK-3475
  • KEYTRUDA®
Drug: 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.
Other Name: PARAPLATIN®
Drug: Paclitaxel
On Days 1, 8 and 15 of Cycles 1-4 in the neoadjuvant phase of the study; IV infusion.
Other Name: TAXOL®
Drug: Doxorubicin
On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV injection.
Other Name: ADRIAMYCIN®
Drug: Epirubicin
On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV injection.
Other Name: ELLENCE®
Drug: Cyclophosphamide
On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV infusion.
Other Name: CYTOXAN®
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.
Drug: 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.
Other Name: PARAPLATIN®
Drug: Paclitaxel
On Days 1, 8 and 15 of Cycles 1-4 in the neoadjuvant phase of the study; IV infusion.
Other Name: TAXOL®
Drug: Doxorubicin
On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV injection.
Other Name: ADRIAMYCIN®
Drug: Epirubicin
On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV injection.
Other Name: ELLENCE®
Drug: Cyclophosphamide
On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV infusion.
Other Name: CYTOXAN®
Drug: Placebo
normal saline solution: On Day 1 of each cycle in the neoadjuvant and adjuvant phases of the study for a total of 17 cycles; IV infusion

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 American Joint Committee of Cancer (AJCC) Breast Cancer Staging 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
  • 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 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).
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03036488


Contacts
Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com

  Show 172 Study Locations
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.
  More Information

Additional Information:
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT03036488     History of Changes
Other Study ID Numbers: 3475-522
2016-004740-11 ( EudraCT Number )
173567 ( Registry Identifier: JAPIC-CTI )
First Submitted: January 27, 2017
First Posted: January 30, 2017
Last Update Posted: November 16, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

http://www.merck.com/clinical-trials/pdf/Merck%20Procedure%20on%20Clinical%20Trial%20Data%20Access%20Final_Updated%20July_9_2014.pdf

http://engagezone.msd.com/ds_documentation.php

URL: http://

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Merck Sharp & Dohme Corp.:
PD1
PD-1
PDL1
PD-L1

Additional relevant MeSH terms:
Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Liposomal doxorubicin
Pembrolizumab
Albumin-Bound Paclitaxel
Cyclophosphamide
Carboplatin
Doxorubicin
Epirubicin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors