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

Esophageal Carcinoma Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03933449
• Other study ID #: 3475-181 China Extension
• Secondary ID: 163145MK-3475-18
• Status: Completed
• Phase: Phase 3
• Start date: December 29, 2016
• Est. completion date: March 14, 2022

Study information

• Verified date: March 2023
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 123
• Est. completion date: March 14, 2022
• Est. primary completion date: February 13, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 ribonucleic acid (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 ~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.

Related Conditions & MeSH terms

• Carcinoma
• Esophageal Carcinoma
• Esophageal Neoplasms
• Esophagogastric Junction Carcinoma

Intervention

Biological:
• pembrolizumab
IV infusion

Drug:
• paclitaxel
IV infusion
• docetaxel
IV infusion
• irinotecan
IV infusion

Locations

Country	Name	City	State
China	Beijing Cancer Hospital ( Site 0700)	Beijing
China	Chinese PLA General Hospital (Site 0703)	Beijing
China	Peking Union Medical College Hospital ( Site 0712)	Beijing
China	The First Hospital Of Jilin University ( Site 0719)	Chang chun	Jilin
China	Jilin Cancer Hospital ( Site 0718)	Changchun	Jilin
China	Hunan Cancer Hospital ( Site 0722)	Changsha	Hunan
China	Fujian Medical University Union Hospital ( Site 0721)	Fuzhou
China	Fujian Province Cancer Hospital ( ( Site 0717)	Fuzhou
China	Sir Sun Sun Shaw Hosp, Zhejiang Univ,Oncology dept. ( Site 0720)	Hangzhou
China	The Second Affiliated Hospital of Zhejiang University School of Medicine ( Site 0705)	Hangzhou
China	Zhejiang Cancer Hospital ( Site 0726)	Hangzhou	Zhejiang
China	Harbin Medical University Cancer Hospital ( Site 0714)	Harbin	Heilongjiang
China	Anhui Provincial Hospital ( Site 0708)	Hefei	Anhui
China	The First Affiliated Hospital of Anhui Medical University ( Site 0707)	Hefei	Anhui
China	Jiangsu Cancer Hospital (Site 0704)	Nanjing	Jiangsu
China	PLA Cancer Centre of Nanjing Bayi Hospital ( Site 0706)	Nanjing	Jiangsu
China	The Affiliated Hospital of Qingdao University ( Site 0709)	Qingdao
China	Fudan University Shanghai Cancer Center ( Site 0723)	Shanghai
China	Ruijin Hospital, Shanghai Jiaotong University ( Site 0701)	Shanghai
China	Shanghai Chest Hospital ( Site 0727)	Shanghai
China	Zhongshan Hospital affiliated to Fudan University ( Site 0715)	Shanghai
China	Wuhan Tongji Hospital ( Site 0724)	Wuhan	Hubei
China	Henan Cancer Hospital ( Site 0725)	Zhengzhou

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Country where clinical trial is conducted

China, 

References & Publications (1)

Cao Y, Qin S, Luo S, Li Z, Cheng Y, Fan Y, Sun Y, Yin X, Yuan X, Li W, Liu T, Hsu CH, Lin X, Kim SB, Kojima T, Zhang J, Lee SH, Bai Y, Muro K, Doi T, Bai C, Gu K, Pan HM, Bai L, Yang JW, Cui Y, Lu W, Chen J. Pembrolizumab versus chemotherapy for patients — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS) in All Participants	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.	From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
Primary	Overall Survival (OS) in Participants With Programmed Death-Ligand 1 Combined Positive Score =10 (PD-L1 CPS =10)	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.	From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
Primary	Overall Survival (OS) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus	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.	From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
Secondary	Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants	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 by central imaging vendor review. The percentage of all participants who experienced a CR or PR for the first pembrolizumab course is presented.	From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
Secondary	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)	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 by central imaging vendor review. The percentage of participants with a PD-L1 CPS =10 who experienced a CR or PR for the first pembrolizumab course is presented.	From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
Secondary	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	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 by central imaging vendor review. The percentage of participants with SCC of the esophagus who experienced a CR or PR for the first pembrolizumab course is presented.	From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
Secondary	Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants	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 for the first pembrolizumab course as assessed by central imaging vendor review per RECIST 1.1 in all participants is presented.	From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
Secondary	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)	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 for the first pembrolizumab course as assessed by central imaging vendor review per RECIST 1.1 is presented for participants with a PD-L1 CPS =10.	From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
Secondary	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	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 for the first pembrolizumab course as assessed by central imaging vendor review per RECIST 1.1 is presented for participants with SCC of the esophagus.	From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
Secondary	Number of Participants Experiencing an Adverse Event (AE)	An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. The number of participants who experienced =1 AE for the first pembrolizumab course are presented.	From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
Secondary	Number of Participants Discontinuing Study Treatment Due an Adverse Event (AE)	An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. The number of participants who discontinued study treatment due to an AE for the first pembrolizumab course are presented.	From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)

External Links

•   Merck Oncology Clinical Trial Information