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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02564263
Recruitment Status : Active, not recruiting
First Posted : September 30, 2015
Last Update Posted : May 8, 2019
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:
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 has progressed after first-line standard therapy will be randomized to receive either single agent pembrolizumab or the Investigator's choice of standard therapy with paclitaxel, docetaxel, or irinotecan. The primary study hypothesis is that treatment with pembrolizumab will prolong overall survival (OS) as compared to treatment with standard therapy.

Condition or disease Intervention/treatment Phase
Esophageal Carcinoma Esophagogastric Junction Carcinoma Biological: pembrolizumab Drug: paclitaxel Drug: docetaxel Drug: irinotecan Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 628 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : December 1, 2015
Actual Primary Completion Date : October 15, 2018
Estimated Study Completion Date : December 31, 2020

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Pembrolizumab
Participants receive pembrolizumab 200 mg, intravenously (IV) on Day 1 of every 21-day (3-week) cycle (Q3W) for up to 35 administrations (approximately 2 years)
Biological: pembrolizumab
Other Names:
  • MK-3475

Active Comparator: Standard Therapy
Participants receive 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
Drug: paclitaxel
IV on Days 1, 8, and 15 of every 28-day (4-week) cycle

Drug: docetaxel
IV on Day 1 of every 21-day (3-week) cycle

Drug: irinotecan
IV on Day 1 of every 14-day (2-week) cycle

Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: Up to 5 years ]

Secondary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: Up to 5 years ]
  2. Progression-free Survival (PFS) [ Time Frame: Up to 5 years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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
  • Known history of or is positive for hepatitis B (hepatitis B surface antigen reactive) or known active hepatitis C (hepatitis C virus RNA or hepatitis C antibody is detected)
  • 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 therapy
  • Has ascites or pleural effusion by physical exam
  • Has experienced documented objective radiographic or clinical disease progression during or after receiving more than 1 line of therapy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02564263

Sponsors and Collaborators
Merck Sharp & Dohme Corp.
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Study Director: Medical Director Merck Sharp & Dohme Corp.

Additional Information:
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Responsible Party: Merck Sharp & Dohme Corp. Identifier: NCT02564263     History of Changes
Other Study ID Numbers: 3475-181
2015-002782-32 ( EudraCT Number )
163145 ( Registry Identifier: JAPAN-CTI )
First Posted: September 30, 2015    Key Record Dates
Last Update Posted: May 8, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Merck Sharp & Dohme Corp.:
Gene expression profiling (GEP)
Additional relevant MeSH terms:
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Esophageal Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors