A Phase III Randomized Open-Label Study of Single Agent Pembrolizumab vs Physicians' Choice of Single Agent Docetaxel, Paclitaxel, or Irinotecan in Subjects With Advanced/Metastatic Adenocarcinoma and Squamous Cell Carcinoma of the Esophagus That Have Progressed After First-Line Standard Therapy (KEYNOTE-181)
Overview
- Phase
- Phase 3
- Intervention
- pembrolizumab
- Conditions
- Esophageal Carcinoma
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 123
- Locations
- 23
- Primary Endpoint
- Overall Survival (OS) in All Participants
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
In the China extension study, Chinese participants with advanced or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of the esophagogastric junction (EGJ) that has progressed after first-line standard therapy will be randomized to receive either single agent pembrolizumab or the Investigator's choice of chemotherapy with paclitaxel, docetaxel, or irinotecan.
The primary extension study hypothesis is that treatment with pembrolizumab will prolong overall survival (OS) as compared to treatment with chemotherapy.
Detailed Description
The China extension study will include participants previously enrolled in China in the global study for MK-3475-181 (NCT02564263) plus those enrolled during the China extension enrollment period. Per protocol, response/progression or adverse events during the second pembrolizumab course will not be counted towards efficacy outcome measures or safety outcome measures.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically- or cytologically-confirmed diagnosis of adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of the EGJ
- •Metastatic disease or locally advanced, unresectable disease
- •Life expectancy of greater than 3 months
- •Measurable disease based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1
- •Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale
- •Documented radiographic or clinical disease progression on no more or less than one previous line of standard therapy
- •Can provide either a newly obtained or archival tumor tissue sample for intra-tumoral immune-related testing and for anti-programmed cell death (PD)-1
- •Participants of reproductive potential must be willing to use adequate contraception for the course of the study through 120 days after the last dose of pembrolizumab or through 180 days after the last dose of paclitaxel, docetaxel or irinotecan
- •Adequate organ function
Exclusion Criteria
- •Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study medication
- •Active autoimmune disease that has required systemic treatment in past 2 years
- •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 medication
- •Known central nervous system (CNS) metastases and/or carcinomatous meningitis (includes past history or current metastasis)
- •Has received prior anti-cancer monoclonal antibody (mAb), chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or not recovered from adverse events due to a previously administered agent
- •Has had a severe hypersensitivity reaction to treatment with another mAb
- •Prior therapy with a PD-1, anti-PD-Ligand 1 (PD-L1), or anti-PD-L2 agent, or previously participated in Merck pembrolizumab (MK-3475) study
- •Has a known additional malignancy that has progressed or required active treatment within the last 5 years with the exception of curatively treated basal cell and squamous cell carcinoma of the skin and/or curatively resected in-situ cervical and/or breast cancers, and in-situ or intra-mucosal pharyngeal cancer
- •Received a live vaccine within 30 days of the first dose of study medication
- •Known history of Human Immunodeficiency Virus (HIV) infection
Arms & Interventions
Pembrolizumab
Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to \~2 years). Participants who complete the first course of up to 35 administrations of pembrolizumab (\~2 years) but progress after discontinuation, may be eligible for a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 of each 3-week cycle for up to 17 cycles (up to \~1 year).
Intervention: pembrolizumab
Chemotherapy
Participants receive Investigator's choice of chemotherapy: paclitaxel 80-100 mg/m\^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m\^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m\^2 IV on Day 1 of every 14-day (2-week) cycle (up to \~2 years).
Intervention: paclitaxel
Chemotherapy
Participants receive Investigator's choice of chemotherapy: paclitaxel 80-100 mg/m\^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m\^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m\^2 IV on Day 1 of every 14-day (2-week) cycle (up to \~2 years).
Intervention: docetaxel
Chemotherapy
Participants receive Investigator's choice of chemotherapy: paclitaxel 80-100 mg/m\^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m\^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m\^2 IV on Day 1 of every 14-day (2-week) cycle (up to \~2 years).
Intervention: irinotecan
Outcomes
Primary Outcomes
Overall Survival (OS) in All Participants
Time Frame: From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
OS was defined as the time from randomization to death due to any cause. Median OS for the first pembrolizumab course in all participants is presented.
Overall Survival (OS) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10)
Time Frame: From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
OS was defined as the time from randomization to death due to any cause. Median OS for the first pembrolizumab course in participants with a PD-L1 CPS ≥10 is presented.
Overall Survival (OS) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus
Time Frame: From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
OS was defined as the time from randomization to death due to any cause. Median OS for the first pembrolizumab course in participants with SCC of the esophagus is presented.
Secondary Outcomes
- Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants(From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months))
- Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10)(From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months))
- Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus(From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months))
- Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants(From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months))
- Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10)(From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months))
- Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus(From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months))
- Number of Participants Experiencing an Adverse Event (AE)(From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months))
- Number of Participants Discontinuing Study Treatment Due an Adverse Event (AE)(From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months))