Clinical trial NCT03933449: 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
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Esophageal Carcinoma
Esophagogastric Junction Carcinoma
Keywords: Programmed Cell Death-1 (PD1, PD-1)
Programmed Death-Ligand 1 (PDL1, PD-L1)
Programmed Death-Ligand 2 (PDL2, PD-L2)
Gene expression profiling (GEP)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2019-05-01
Enrollment: 123
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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
* 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.

Primary outcomes:
measure: Overall Survival (OS) in All Participants
timeFrame: From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
measure: Overall Survival (OS) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10)
timeFrame: From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
measure: Overall Survival (OS) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus
timeFrame: From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
Secondary outcomes:
measure: Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants
timeFrame: From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
measure: 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)
timeFrame: From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
measure: 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
timeFrame: From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
measure: Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants
timeFrame: From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
measure: 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)
timeFrame: From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
measure: 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
timeFrame: From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
measure: Number of Participants Experiencing an Adverse Event (AE)
timeFrame: From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
measure: Number of Participants Discontinuing Study Treatment Due an Adverse Event (AE)
timeFrame: From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to ~24 months)
Other outcomes:
Locations:
city: Hefei
country: China
facility: Anhui Provincial Hospital ( Site 0708)
state: Anhui
city: Hefei
country: China
facility: The First Affiliated Hospital of Anhui Medical University ( Site 0707)
state: Anhui
city: Harbin
country: China
facility: Harbin Medical University Cancer Hospital ( Site 0714)
state: Heilongjiang
city: Wuhan
country: China
facility: Wuhan Tongji Hospital ( Site 0724)
state: Hubei
city: Changsha
country: China
facility: Hunan Cancer Hospital ( Site 0722)
state: Hunan
city: Nanjing
country: China
facility: Jiangsu Cancer Hospital (Site 0704)
state: Jiangsu
city: Nanjing
country: China
facility: PLA Cancer Centre of Nanjing Bayi Hospital ( Site 0706)
state: Jiangsu
city: Chang chun
country: China
facility: The First Hospital Of Jilin University ( Site 0719)
state: Jilin
city: Changchun
country: China
facility: Jilin Cancer Hospital ( Site 0718)
state: Jilin
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital ( Site 0726)
state: Zhejiang
city: Beijing
country: China
facility: Beijing Cancer Hospital ( Site 0700)
city: Beijing
country: China
facility: Chinese PLA General Hospital (Site 0703)
city: Beijing
country: China
facility: Peking Union Medical College Hospital ( Site 0712)
city: Fuzhou
country: China
facility: Fujian Medical University Union Hospital ( Site 0721)
city: Fuzhou
country: China
facility: Fujian Province Cancer Hospital ( ( Site 0717)
city: Hangzhou
country: China
facility: The Second Affiliated Hospital of Zhejiang University School of Medicine ( Site 0705)
city: Hangzhou
country: China
facility: Sir Sun Sun Shaw Hosp, Zhejiang Univ,Oncology dept. ( Site 0720)
city: Qingdao
country: China
facility: The Affiliated Hospital of Qingdao University ( Site 0709)
city: Shanghai
country: China
facility: Ruijin Hospital, Shanghai Jiaotong University ( Site 0701)
city: Shanghai
country: China
facility: Shanghai Chest Hospital ( Site 0727)
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center ( Site 0723)
city: Shanghai
country: China
facility: Zhongshan Hospital affiliated to Fudan University ( Site 0715)
city: Zhengzhou
country: China
facility: Henan Cancer Hospital ( Site 0725)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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 with esophageal squamous cell carcinoma enrolled in the randomized KEYNOTE-181 trial in Asia. ESMO Open. 2022 Feb;7(1):100341. doi: 10.1016/j.esmoop.2021.100341. Epub 2021 Dec 29.