Study of Pembrolizumab (MK-3475) Versus Investigator's Choice Standard Therapy for Participants With Advanced Esophageal/ Esophagogastric Junction Carcinoma That Progressed After First-Line Therapy (MK-3475-181/KEYNOTE-181)

February 9, 2023 updated by: Merck Sharp & Dohme LLC

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)

In this study, participants with advanced or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of the esophagogastric junction (EGJ) that had progressed after first-line standard therapy were randomized to receive either pembrolizumab (MK-3475) OR the Investigator's choice of standard chemotherapy with paclitaxel, docetaxel, or irinotecan.

The primary study hypothesis was that treatment with pembrolizumab would prolong overall survival (OS) as compared to treatment with standard chemotherapy.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
628

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 3

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 treatment
  • 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 treatment
  • 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 treatment
  • Known history of human immunodeficiency virus (HIV) infection
  • Known history of or is positive for hepatitis B or known active hepatitis C
  • History of non-infectious pneumonitis that required steroids or current pneumonitis
  • Active infection requiring systemic therapy
  • Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study
  • 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 pembrolizumab or through 180 days after the last dose of paclitaxel, docetaxel or irinotecan
  • Known allergy, hypersensitivity, or contraindication to paclitaxel, docetaxel, or irinotecan or any components used in their preparation
  • Experienced weight loss >10% over approximately 2 months prior to first dose of study treatment
  • Has ascites or pleural effusion by physical exam
  • Has experienced documented objective radiographic or clinical disease progression during or after receiving >1 line of therapy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Pembrolizumab
Participants received pembrolizumab 200 mg, intravenously (IV) on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months).
Biological: pembrolizumab
200 mg administered as IV infusion on Day 1 of every 21-day cycle
Other Names:
  • MK-3475
  • KEYTRUDA®
Active Comparator: Chemotherapy
Participants received Investigator's choice of 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 approximately 19 months).
Drug: paclitaxel
80-100 mg/m^2 administered as IV infusion on Days 1, 8, and 15 of each 28-day cycle
Other Names:
  • TAXOL®
Drug: docetaxel
75 mg/m^2 administered as IV infusion on Day 1 of every 21-day cycle
Other Names:
  • TAXOTERE®
Drug: irinotecan
180 mg/m^2 administered as IV infusion on Day 1 of every 14-day cycle
Other Names:
  • CAMPTOSAR®

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Overall Survival (OS) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus
Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
OS was defined as the time from randomization to death due to any cause. Median OS in participants with SCC of the esophagus is presented.
Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
Overall Survival (OS) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10)
Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
OS was defined as the time from randomization to death due to any cause. Median OS in participants with a PD-L1 CPS ≥10 is presented.
Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
Overall Survival (OS) in All Participants
Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
OS was defined as the time from randomization to death due to any cause. Median OS in all participants is presented.
Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants
Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS as assessed by blinded independent central review per RECIST 1.1 in all participants is presented.
Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants
Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
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 the sum of diameters of target lesions) as assessed using RECIST 1.1. The percentage of all participants who experienced a CR or PR is presented.
Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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
Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS as assessed by blinded independent central review per RECIST 1.1 is presented for participants with SCC of the esophagus.
Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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)
Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS as assessed by blinded independent central review per RECIST 1.1 is presented for participants with a PD-L1 CPS ≥10.
Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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
Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
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 the sum of diameters of target lesions) as assessed using RECIST 1.1. The percentage of participants with SCC of the esophagus who experienced a CR or PR is presented.
Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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)
Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
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 the sum of diameters of target lesions) as assessed using RECIST 1.1. The percentage of participants with a PD-L1 CPS ≥10 who experienced a CR or PR is presented.
Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
Number of Participants Experiencing an Adverse Event (AE)
Time Frame: Through End-of-Trial Analysis data cutoff date of 14-Mar-2022 (up to approximately 6 years)
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. The number of participants who experienced ≥1 AE is presented.
Through End-of-Trial Analysis data cutoff date of 14-Mar-2022 (up to approximately 6 years)
Number of Participants Discontinuing Study Treatment Due an Adverse Event (AE)
Time Frame: Through End-of-Trial Analysis data cutoff date of 14-Mar-2022 (up to approximately 6 years)
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. The number of participants who discontinued study treatment due to an AE is presented.
Through End-of-Trial Analysis data cutoff date of 14-Mar-2022 (up to approximately 6 years)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Merck Sharp & Dohme LLC

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 1, 2015

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
October 15, 2018

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 14, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
September 29, 2015

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 29, 2015

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
September 30, 2015

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 13, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 9, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 3475-181
  • 163145 (Registry Identifier: JAPAN-CTI)
  • MK-3475-181 (Other Identifier: Merck)
  • KEYNOTE-181 (Other Identifier: Merck)
  • 2015-002782-32 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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