Clinical Trials /

Study of Pembrolizumab (MK-3475) Monotherapy for Metastatic Triple-Negative Breast Cancer (MK-3475-086/KEYNOTE-086)

NCT02447003

Description:

This is a two-part study of pembrolizumab monotherapy in participants with metastatic triple-negative breast cancer (mTNBC). Part 1 of the study will examine the efficacy and safety of pembrolizumab monotherapy as first line or above treatment in participants who have received either no prior systemic treatment or at least one prior systemic treatment for metastatic breast cancer. Part 2 of the study, if done, will expand the investigation of pembrolizumab treatment in a subgroup of participants from Part 1 and will only start after enrollment in Part 1 has been completed. There will be no hypothesis testing in this study.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Pembrolizumab (MK-3475) Monotherapy for Metastatic Triple-Negative Breast Cancer (MK-3475-086/KEYNOTE-086)
  • Official Title: A Phase II Clinical Trial of Pembrolizumab (MK-3475) as Monotherapy for Metastatic Triple-Negative Breast Cancer (mTNBC) - (KEYNOTE-086)

Clinical Trial IDs

  • ORG STUDY ID: 3475-086
  • SECONDARY ID: 2015-000294-13
  • SECONDARY ID: 152987
  • NCT ID: NCT02447003

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
PembrolizumabMK-3475, KEYTRUDA®Cohort A: Pembrolizumab

Purpose

This is a two-part study of pembrolizumab monotherapy in participants with metastatic triple-negative breast cancer (mTNBC). Part 1 of the study will examine the efficacy and safety of pembrolizumab monotherapy as first line or above treatment in participants who have received either no prior systemic treatment or at least one prior systemic treatment for metastatic breast cancer. Part 2 of the study, if done, will expand the investigation of pembrolizumab treatment in a subgroup of participants from Part 1 and will only start after enrollment in Part 1 has been completed. There will be no hypothesis testing in this study.

Detailed Description

      Qualified participants who complete up to ~2 years of pembrolizumab treatment but progress
      after discontinuation may be eligible for a second course of pembrolizumab for up to ~1
      additional year, at the Investigator's discretion. Per protocol, response or progression
      during this second course will not count towards efficacy outcome measure and adverse events
      during this second course will not count towards safety outcome measures.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort A: PembrolizumabExperimentalParticipants in Cohort A previously received at least one prior systemic treatment for metastatic breast cancer. Participants will be administered pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles (up to ~ 2 years).
  • Pembrolizumab
Cohort B: PembrolizumabExperimentalParticipants in Cohort B previously received no prior systemic treatment for metastatic breast cancer AND had a programmed cell death-ligand 1 (PD-L1) positive tumor expression. Participants will be administered pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles (up to ~ 2 years).
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

        For the purposes of this study, neoadjuvant and/or adjuvant chemotherapy regimens do not
        count as a prior line of therapy.

        For second line plus monotherapy (Parts 1 and 2):

          -  Has received at least one systemic treatment for metastatic breast cancer

          -  Has documented disease progression on or after the most recent therapy

          -  Prior treatment must include an anthracycline and a taxane in the neoadjuvant,
             adjuvant, or metastatic setting

        For first line monotherapy (Part 1):

          -  Has received no prior systemic treatment for metastatic breast cancer

          -  Has PD-L1-positive mTNBC.

        For second line plus monotherapy (Part 2):

        - Has PD-L1 strong positive mTNBC

        For all parts:

          -  Has mTNBC confirmed by a central laboratory

          -  For biomarker analysis, adequate newly obtained core or excisional biopsy of a
             not-previously-irradiated metastatic tumor lesion (mandatory)

          -  Has measurable metastatic disease

          -  Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Female participants of childbearing potential should be willing to use 2 methods of
             birth control or be surgically sterile, or abstain from heterosexual activity for the
             course of the study through 120 days after the last dose of study treatment

          -  Male participants should agree to use an adequate method of contraception starting
             with the first dose of study treatment through 120 days after the last dose of study
             treatment

          -  Has adequate organ function

        Exclusion Criteria:

          -  Is currently participating and receiving study treatment, or has participated in a
             study of an investigational agent and received study therapy or used an
             investigational device within 4 weeks prior to study Day 1

          -  Has received prior anti-cancer monoclonal antibody (mAb) therapy for direct
             anti-neoplastic treatment within 4 weeks prior to study Day 1

          -  Has received prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within at least 2 weeks prior to study Day 1

          -  Has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents
             administered within at least 2 weeks prior to study Day 1

          -  Has an active autoimmune disease requiring systemic treatment in past 2 years

          -  Has a diagnosis of immunodeficiency or receiving systemic steroid therapy or any other
             form of immunosuppressive therapy within 7 days prior to the first dose of study
             treatment

          -  Has known additional malignancy that progressed or required active treatment within
             the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell
             carcinoma of the skin that has undergone potentially curative therapy, or in situ
             cervical cancer

          -  Has radiographically-detectable central nervous system (CNS) metastases and/or
             carcinomatous meningitis

          -  Has a history of (non-infectious) pneumonitis that required steroids or current
             pneumonitis or a history of interstitial lung disease

          -  Has an active infection requiring systemic therapy

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the study

          -  Is pregnant, breastfeeding, or expecting to conceive or father children within the
             projected duration of the study, starting with the screening visit through 120 days
             after the last dose of study treatment

          -  Has received prior therapy with an anti-programmed cell death protein-1 (anti-PD-1),
             anti-PD-L1, anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell
             receptor (e.g. cytotoxic T-lymphocyte-associated protein-4 [CTLA-4], OX-40, CD137) or
             has participated in Merck MK-3475 (pembrolizumab) study

          -  Has a known history of human immunodeficiency virus (HIV)

          -  Has known active Hepatitis B or C

          -  Has received a live vaccine within 30 days of planned start of study treatment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Central Imaging Vendor (CIV) in All Cohort A Participants
Time Frame:Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
Safety Issue:
Description:ORR was defined as the percentage of participants who had a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in sum of diameters [SOD] of target lesions) per RECIST 1.1 by CIV. ORR was estimated by Agresti-Coull (A-C) method. The percentage of participants who had CR or PR is reported here as the protocol-specified ORR, for the first pembrolizumab course, assessed from enrolment/treatment initiation and analyzed by Cohort, for all participants in Cohort A. Per protocol final ORR analysis in all Cohort A participants was done at the time of final statistical efficacy analysis, with a 10-November (Nov)-2017 cutoff. Per protocol ORR per RECIST 1.1 by CIV in all Cohort A participants was planned and conducted as a pre-specified primary outcome analysis. Per protocol ORR per RECIST 1.1 by CIV in all Cohort B participants was analyzed separately as a pre-specified secondary outcome analysis and reported later in the record.

Secondary Outcome Measures

Measure:ORR Per RECIST 1.1 by CIV in All Cohort B Participants
Time Frame:Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
Safety Issue:
Description:ORR was defined as the percentage of participants who had a CR (disappearance of all target lesions) or a PR (≥30% decrease in SOD of target lesions) per RECIST 1.1 by CIV. ORR was estimated by A-C method. The percentage of participants who had CR or PR is reported here as the protocol-specified ORR, for the first pembrolizumab course, assessed from enrolment/treatment initiation and analyzed by Cohort for all participants in Cohort B. Per protocol final ORR analysis in all Cohort B participants was done at the time of final statistical efficacy analysis, with a 10-Nov-2017 cutoff. Per protocol ORR per RECIST 1.1 by CIV in all Cohort B participants was planned and conducted as a pre-specified secondary outcome analysis. Per protocol ORR per RECIST 1.1 by CIV in all Cohort A participants was analyzed separately as a pre-specified primary outcome analysis and reported earlier in the record.
Measure:Duration of Response (DOR) Per RECIST 1.1 by CIV in All Cohort A and Cohort B Participants
Time Frame:Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
Safety Issue:
Description:For participants who had CR (disappearance of all target lesions) or PR (≥30% target lesion SOD decrease) per RECIST 1.1 by CIV, DOR was defined as time from first documented CR or PR until progressive disease (PD: ≥20% target lesion SOD increase, ≥5 mm absolute SOD increase; PD is also ≥1 new lesion appearance) or death. DOR for those who didn't progress/die at time of analysis was censored at last tumor assessment. Per protocol DOR for the first pembrolizumab course, assessed from enrolment/treatment initiation, estimated by Kaplan-Meier (KM) method and analyzed by cohort is reported here for all participants in Cohort A and Cohort B who had CR or PR per RECIST 1.1 by CIV. Per protocol final DOR analysis in all Cohort A and Cohort B participants was done at the time of final statistical efficacy analysis with a 10-Nov-2017 cutoff.
Measure:DOR Per RECIST 1.1 by CIV in Subgroup of Cohort A Participants With PD-L1 Positive Tumor Expression
Time Frame:Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
Safety Issue:
Description:For participants who had CR (disappearance of all target lesions) or PR (≥30% target lesion SOD decrease) per RECIST 1.1 by CIV, DOR was defined as time from first documented CR or PR until PD (≥20% target lesion SOD increase, ≥5 mm absolute SOD increase; PD is also ≥1 new lesion appearance) or death. DOR for those who didn't progress/die at time of analysis was censored at last tumor assessment. Per protocol DOR for first pembrolizumab course, assessed from enrolment/treatment initiation, estimated by KM method and analyzed by Cohort is reported here for subgroup of Cohort A participants with tumor IHC defined-PD-L1 positive expression (PD-L1+) and CR/PR per RECIST 1.1 by CIV. Per protocol final DOR analysis in Cohort A PD-L1+ subgroup was done at time of final statistical efficacy analysis with a 10-Nov-2017 cutoff. Per protocol all Cohort B participants were PD-L1+ and DOR per RECIST 1.1 by CIV in all Cohort B participants was analyzed separately and reported earlier in the record
Measure:Disease Control Rate (DCR) Per RECIST 1.1 by CIV in All Cohort A and Cohort B Participants
Time Frame:Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
Safety Issue:
Description:DCR was defined as the percentage of participants in the analysis population who have CR (disappearance of all target lesions) or PR (≥30% target lesion SOD decrease) or SD (not sufficient shrinkage for PR or sufficient increase for PD [≥20% target lesion SOD increase, ≥5 mm absolute SOD increase; PD is also ≥1 new lesion appearance]) for ≥24 weeks per RECIST 1.1 by CIV. Per protocol percentage of participants who had CR, PR or SD per RECIST 1.1 by CIV is reported here as DCR, for the first pembrolizumab course, assessed from enrolment/treatment initiation, estimated by A-C method and analyzed by Cohort, for all participants in Cohort A and Cohort B. Per protocol final DCR analysis in all Cohort A and Cohort B participants was done at the time of final statistical efficacy analysis, with a 10-Nov-2017 cutoff.
Measure:DCR Per RECIST 1.1 by CIV in Subgroup of Cohort A Participants With PD-L1 Positive Tumor Expression
Time Frame:Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
Safety Issue:
Description:DCR was defined as the percentage of participants who have CR (disappearance of all target lesions) or PR (≥30% target lesion SOD decrease) or SD (not sufficient shrinkage for PR or sufficient increase for PD [≥20% target lesion SOD increase, ≥5 mm absolute SOD increase; PD is also ≥1 new lesion appearance]) for ≥24 weeks per RECIST 1.1 by CIV. Per protocol percentage of participants who had CR, PR or SD per RECIST 1.1 by CIV is reported here as DCR for the first pembrolizumab course, assessed from enrolment/treatment initiation, estimated by A-C method and analyzed by Cohort for subgroup of Cohort A participants with tumor IHC defined-PD-L1 positive expression (PD-L1+). Per protocol final DCR analysis in Cohort A PD-L1+ subgroup was done at the time of final statistical efficacy analysis with a 10-Nov-2017 cutoff. Per protocol all Cohort B participants were PD-L1+ and DCR per RECIST 1.1 by CIV in all Cohort B participants was analyzed separately and reported earlier in the record.
Measure:Progression Free Survival (PFS) Per RECIST 1.1 by CIV in All Cohort A and Cohort B Participants
Time Frame:Up to ~28 months (through pre-specified final statistical analysis cut-off date of 10-Nov-2017)
Safety Issue:
Description:PFS was defined as the time from first dose of study drug to the first documented PD per RECIST 1.1 by CIV, or death due to any cause, whichever occurred first. Per RECIST 1.1 PD was defined as ≥20% increase in SOD of target lesions and absolute SOD increase of ≥5 mm. Appearance of ≥1 new lesion is also PD. PFS was estimated by KM method. Per protocol PFS, for the first pembrolizumab course, assessed from enrolment/treatment initiation and analyzed by Cohort is reported here for all participants in Cohort A and Cohort B. Per protocol final PFS analysis in all Cohort A and Cohort B participants was done at the time of final statistical efficacy analysis with a 10-Nov-2017 cutoff.
Measure:PFS Per RECIST 1.1 by CIV in Subgroup of Cohort A Participants With PD-L1 Positive Tumor Expression
Time Frame:Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
Safety Issue:
Description:PFS was defined as the time from first dose of study drug to the first documented PD per RECIST 1.1 by CIV, or death due to any cause, whichever occurred first. Per RECIST 1.1 PD was defined as ≥20% increase in SOD of target lesions and absolute SOD increase of ≥5 mm. Appearance of ≥1 new lesion is also PD. PFS was estimated by KM method. Per protocol PFS, for the first pembrolizumab course, assessed from enrolment/treatment initiation and analyzed by Cohort is reported here for the subgroup of Cohort A participants with tumor IHC defined-PD-L1 positive expression (PD-L1+). Per protocol final PFS analysis in the Cohort A PD-L1+ subgroup was done at the time of final statistical efficacy analysis with a 10-Nov-2017 cutoff. Per protocol all Cohort B participants were PD-L1+ and PFS per RECIST 1.1 by CIV in all Cohort B participants was analyzed separately and reported earlier in the record.
Measure:Overall Survival (OS) in All Cohort A and Cohort B Participants
Time Frame:Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
Safety Issue:
Description:OS was defined as the time from the first dose of study drug to death due to any cause. OS was estimated by KM method. Per protocol OS, for the first pembrolizumab course, assessed from enrolment/treatment initiation and analyzed by Cohort is reported here for all participants in Cohort A and Cohort B. Per protocol final OS analysis in all Cohort A and Cohort B participants was done at the time of final statistical efficacy analysis with a 10-Nov-2017 cutoff.
Measure:OS in Subgroup of Cohort A Participants With PD-L1 Positive Tumor Expression
Time Frame:Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
Safety Issue:
Description:OS was defined as the time from the first dose of study drug to death due to any cause. OS was estimated by KM method. Per protocol OS, for the first pembrolizumab course, assessed from enrolment/treatment initiation and analyzed by Cohort, is reported here for the subgroup of Cohort A participants with tumor IHC defined-PD-L1 positive expression (PD-L1+). Per protocol final OS analysis in the Cohort A PD-L1+ subgroup was done at the time of final statistical efficacy analysis with a 10-Nov-2017 cutoff. Per protocol all Cohort B participants were PD-L1+ and OS in all Cohort B participants was analyzed separately and reported earlier in the record.
Measure:Odds Ratio of Association Between PD-L1 Tumor Expression and Objective Response (OR) Per RECIST 1.1 by CIV in Cohort A Participants
Time Frame:Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
Safety Issue:
Description:OR comprises CR (disappearance of all target lesions) or PR (≥30% target lesion SOD decrease) per RECIST 1.1 by CIV. PD-L1 expression is assessed by IHC-defined combined positive score (CPS). Association between (b/w) PD-L1 CPS and OR was assessed by odds ratio using a logistic regression model and was calculated as ratio of odds of OR per unit CPS increase in a single arm (odds ratio=1: no association; odds ratio<1: negative association [increase in CPS lowers odds of OR]; odds ratio >1: positive association [increase in CPS raises odds of OR]). Per protocol odds ratio, for the first pembrolizumab course, assessed from enrolment/treatment initiation and analyzed by Cohort is reported here in a single arm of Cohort A participants with PD-L1 CPS available. Per protocol odds ratio was analyzed at the time of final statistical efficacy analysis with a 10-Nov-2017 cutoff. Per protocol odds ratio of association b/w PD-L1 expression and OR was not planned or done in Cohort B participants.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • Programmed Cell Death-1 (PD1, PD-1)
  • Programmed Death-Ligand 1 (PDL1, PD-L1)

Last Updated

December 16, 2020