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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)

NCT03036488

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief 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)
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: 3475-522
  • SECONDARY ID: 2016-004740-11
  • SECONDARY ID: 173567
  • NCT ID: NCT03036488

Conditions

  • Triple Negative Breast Neoplasms

Interventions

DrugSynonymsArms
PembrolizumabMK-3475, KEYTRUDA®Pembrolizumab + Chemotherapy
CarboplatinPARAPLATIN®Pembrolizumab + Chemotherapy
PaclitaxelTAXOL®Pembrolizumab + Chemotherapy
DoxorubicinADRIAMYCIN®Pembrolizumab + Chemotherapy
EpirubicinELLENCE®Pembrolizumab + Chemotherapy
CyclophosphamideCYTOXAN®Pembrolizumab + Chemotherapy
PlaceboPlacebo + Chemotherapy

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.

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab + ChemotherapyExperimentalParticipants 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.
  • Carboplatin
  • Paclitaxel
  • Doxorubicin
  • Epirubicin
  • Cyclophosphamide
Placebo + ChemotherapyActive ComparatorParticipants 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.
  • Carboplatin
  • Paclitaxel
  • Doxorubicin
  • Epirubicin
  • Cyclophosphamide
  • Placebo

Eligibility 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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure:EFS in participants with tumors expressing PD-L1
Time Frame:Up to approximately 8 years
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure:Overall survival (OS)
Time Frame:Up to approximately 8 years
Safety Issue:
Description: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.
Measure:Percentage of participants who experience an adverse event (AE)
Time Frame:Up to approximately 61 weeks
Safety Issue:
Description: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.
Measure:Percentage of participants who discontinue study treatment due to an AE
Time Frame:Up to approximately 57 weeks
Safety Issue:
Description: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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • PD1
  • PD-1
  • PDL1
  • PD-L1

Last Updated

June 14, 2017