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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT02447003
Registration number
NCT02447003
Ethics application status
Date submitted
14/05/2015
Date registered
18/05/2015
Date last updated
16/12/2020
Titles & IDs
Public title
Study of Pembrolizumab (MK-3475) Monotherapy for Metastatic Triple-Negative Breast Cancer (MK-3475-086/KEYNOTE-086)
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Scientific title
A Phase II Clinical Trial of Pembrolizumab (MK-3475) as Monotherapy for Metastatic Triple-Negative Breast Cancer (mTNBC) - (KEYNOTE-086)
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Secondary ID [1]
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2015-000294-13
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Secondary ID [2]
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3475-086
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Breast Cancer
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Condition category
Condition code
Cancer
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Breast
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Other interventions - Pembrolizumab
Experimental: Cohort A: Pembrolizumab - Participants 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).
Experimental: Cohort B: Pembrolizumab - Participants 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).
Other interventions: Pembrolizumab
IV infusion of 200 mg.
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Intervention code [1]
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Other interventions
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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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
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Assessment method [1]
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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.
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Timepoint [1]
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Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
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Primary outcome [2]
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ORR Per RECIST 1.1 by CIV in Subgroup of Cohort A Participants With Programmed Cell Death- Ligand 1 (PD-L1) Positive Tumor Expression
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Assessment method [2]
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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 the subgroup of Cohort A participants with tumor immunohistochemistry (IHC) defined-PD-L1 positive expression (PD-L1+). Per protocol final ORR 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 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.
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Timepoint [2]
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Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
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Primary outcome [3]
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Number of Participants Who Experienced at Least One Adverse Event (AE)
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Assessment method [3]
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An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that is temporally associated with the use of the Sponsor's product is also an AE. Per protocol the number of participants who experienced at least one AE, for the first pembrolizumab course, was assessed from enrollment/treatment initiation of a participant and analyzed by Cohort and is reported here for all participants in Cohort A and Cohort B who received =1 dose of study drug.
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Timepoint [3]
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Up to ~31 months
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Primary outcome [4]
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Number of Participants Who Discontinued Study Drug Due to an AE
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Assessment method [4]
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An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that is temporally associated with the use of the Sponsor's product is also an AE. Per protocol the number of participants who discontinued study drug due to an AE, in the first pembrolizumab course, was assessed from enrolment/treatment initiation of a participant and analyzed by Cohort and is reported here for all participants in Cohort A and Cohort B who received =1 dose of study drug.
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Timepoint [4]
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Up to ~31 months
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Secondary outcome [1]
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ORR Per RECIST 1.1 by CIV in All Cohort B Participants
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Assessment method [1]
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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.
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Timepoint [1]
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Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
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Secondary outcome [2]
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Duration of Response (DOR) Per RECIST 1.1 by CIV in All Cohort A and Cohort B Participants
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Assessment method [2]
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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.
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Timepoint [2]
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Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
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Secondary outcome [3]
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DOR Per RECIST 1.1 by CIV in Subgroup of Cohort A Participants With PD-L1 Positive Tumor Expression
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Assessment method [3]
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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
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Timepoint [3]
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Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
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Secondary outcome [4]
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Disease Control Rate (DCR) Per RECIST 1.1 by CIV in All Cohort A and Cohort B Participants
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Assessment method [4]
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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.
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Timepoint [4]
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Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
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Secondary outcome [5]
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DCR Per RECIST 1.1 by CIV in Subgroup of Cohort A Participants With PD-L1 Positive Tumor Expression
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Assessment method [5]
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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.
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Timepoint [5]
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Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
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Secondary outcome [6]
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Progression Free Survival (PFS) Per RECIST 1.1 by CIV in All Cohort A and Cohort B Participants
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Assessment method [6]
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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.
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Timepoint [6]
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Up to ~28 months (through pre-specified final statistical analysis cut-off date of 10-Nov-2017)
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Secondary outcome [7]
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PFS Per RECIST 1.1 by CIV in Subgroup of Cohort A Participants With PD-L1 Positive Tumor Expression
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Assessment method [7]
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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.
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Timepoint [7]
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Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
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Secondary outcome [8]
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Overall Survival (OS) in All Cohort A and Cohort B Participants
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Assessment method [8]
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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.
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Timepoint [8]
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Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
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Secondary outcome [9]
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OS in Subgroup of Cohort A Participants With PD-L1 Positive Tumor Expression
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Assessment method [9]
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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.
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Timepoint [9]
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Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
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Secondary outcome [10]
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Odds Ratio of Association Between PD-L1 Tumor Expression and Objective Response (OR) Per RECIST 1.1 by CIV in Cohort A Participants
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Assessment method [10]
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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.
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Timepoint [10]
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Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
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Eligibility
Key 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
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
11/06/2015
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
31/01/2020
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Sample size
Target
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Accrual to date
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Final
254
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Recruitment in Australia
Recruitment state(s)
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Merck Sharp & Dohme LLC
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT02447003
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Trial related presentations / publications
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Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed
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Contacts
Principal investigator
Name
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Medical Director
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Address
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Merck Sharp & Dohme LLC
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02447003
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