Clinical trial NCT02447003: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: Programmed Cell Death-1 (PD1, PD-1)
Programmed Death-Ligand 1 (PDL1, PD-L1)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2015-05-18
Enrollment: 254
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

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

Primary outcomes:
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
timeFrame: Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
measure: ORR Per RECIST 1.1 by CIV in Subgroup of Cohort A Participants With Programmed Cell Death- Ligand 1 (PD-L1) Positive Tumor Expression
timeFrame: Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
measure: Number of Participants Who Experienced at Least One Adverse Event (AE)
timeFrame: Up to ~31 months
measure: Number of Participants Who Discontinued Study Drug Due to an AE
timeFrame: Up to ~31 months
Secondary outcomes:
measure: ORR Per RECIST 1.1 by CIV in All Cohort B Participants
timeFrame: Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
measure: Duration of Response (DOR) Per RECIST 1.1 by CIV in All Cohort A and Cohort B Participants
timeFrame: Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
measure: DOR Per RECIST 1.1 by CIV in Subgroup of Cohort A Participants With PD-L1 Positive Tumor Expression
timeFrame: Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
measure: Disease Control Rate (DCR) Per RECIST 1.1 by CIV in All Cohort A and Cohort B Participants
timeFrame: Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
measure: DCR Per RECIST 1.1 by CIV in Subgroup of Cohort A Participants With PD-L1 Positive Tumor Expression
timeFrame: Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
measure: Progression Free Survival (PFS) Per RECIST 1.1 by CIV in All Cohort A and Cohort B Participants
timeFrame: Up to ~28 months (through pre-specified final statistical analysis cut-off date of 10-Nov-2017)
measure: PFS Per RECIST 1.1 by CIV in Subgroup of Cohort A Participants With PD-L1 Positive Tumor Expression
timeFrame: Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
measure: Overall Survival (OS) in All Cohort A and Cohort B Participants
timeFrame: Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
measure: OS in Subgroup of Cohort A Participants With PD-L1 Positive Tumor Expression
timeFrame: Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
measure: Odds Ratio of Association Between PD-L1 Tumor Expression and Objective Response (OR) Per RECIST 1.1 by CIV in Cohort A Participants
timeFrame: Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Cristescu R, Aurora-Garg D, Albright A, Xu L, Liu XQ, Loboda A, Lang L, Jin F, Rubin EH, Snyder A, Lunceford J. Tumor mutational burden predicts the efficacy of pembrolizumab monotherapy: a pan-tumor retrospective analysis of participants with advanced solid tumors. J Immunother Cancer. 2022 Jan;10(1):e003091. doi: 10.1136/jitc-2021-003091.
citation: Adams S, Schmid P, Rugo HS, Winer EP, Loirat D, Awada A, Cescon DW, Iwata H, Campone M, Nanda R, Hui R, Curigliano G, Toppmeyer D, O'Shaughnessy J, Loi S, Paluch-Shimon S, Tan AR, Card D, Zhao J, Karantza V, Cortes J. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study. Ann Oncol. 2019 Mar 1;30(3):397-404. doi: 10.1093/annonc/mdy517.
citation: Adams S, Loi S, Toppmeyer D, Cescon DW, De Laurentiis M, Nanda R, Winer EP, Mukai H, Tamura K, Armstrong A, Liu MC, Iwata H, Ryvo L, Wimberger P, Rugo HS, Tan AR, Jia L, Ding Y, Karantza V, Schmid P. Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study. Ann Oncol. 2019 Mar 1;30(3):405-411. doi: 10.1093/annonc/mdy518.
citation: Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, Pusztai L, Pathiraja K, Aktan G, Cheng JD, Karantza V, Buisseret L. Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol. 2016 Jul 20;34(21):2460-7. doi: 10.1200/JCO.2015.64.8931. Epub 2016 May 2.