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First-line Esophageal Carcinoma Study With Chemo vs. Chemo Plus Pembrolizumab (MK-3475-590/KEYNOTE-590)

Primary Purpose

Esophageal Neoplasms

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Pembrolizumab

Placebo

Cisplatin

5-FU

About this trial

This is an interventional treatment trial for Esophageal Neoplasms focused on measuring Programmed Cell Death-1 (PD1, PD-1),, Programmed Cell Death Receptor Ligand 1 (PDL1, PD-L1), Programmed Cell Death Receptor Ligand 2 (PDL2, PD-L2)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Has histologically- or cytologically-confirmed diagnosis of locally advanced unresectable or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the esophagogastric junction (EGJ)
Has measurable disease per RECIST 1.1 as determined by the local site investigator/radiology assessment
Eastern Cooperative Group (ECOG) performance status of 0 to 1
Can provide either a newly obtained or archival tissue sample for PD-L1 by immunohistochemistry analysis
Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to randomization and be willing to use an adequate method of contraception (e.g. abstinence, intrauterine device, diaphragm with spermicide, etc.) for the course of the study through 120 days after the last dose of study treatment and up to 180 days after last dose of cisplatin
Male participants of childbearing potential must agree to use an adequate method of contraception (e.g. abstinence, vasectomy, male condom, etc.) starting with the first dose of study treatment through 120 days after the last dose of study treatment and up to 180 days after last dose of cisplatin, and refrain from donating sperm during this period
Has adequate organ function

Exclusion Criteria:

Has locally advanced esophageal carcinoma that is resectable or potentially curable with radiation therapy (as determined by local investigator)
Has had previous therapy for advanced/metastatic adenocarcinoma or squamous cell cancer of the esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the EGJ
Has had major surgery, open biopsy, or significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgery during the course of study treatment
Has a known additional malignancy that is progressing or requires active treatment. Exceptions include early-stage cancers (carcinoma in situ or Stage 1) treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, in situ breast cancer that has undergone potentially curative therapy, and in situ or intramucosal pharyngeal cancer
Has known active central nervous system metastases and/or carcinomatous meningitis.
Has an active autoimmune disease that has required systemic treatment in past 2 years
Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment, or has a history of organ transplant, including allogeneic stem cell transplant
Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis, or has an active infection requiring systemic therapy
Is pregnant or 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 study medication and up to 180 days after last dose of cisplatin
Has received prior therapy with an anti-programmed cell death protein-1 (anti-PD-1), anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor or has previously participated in a pembrolizumab (MK-3475) clinical trial
Has severe hypersensitivity (≥ Grade 3) to any study treatment (pembrolizumab, cisplatin, or 5-FU) and/or any of its excipients
Has a known history of active tuberculosis (TB; Mycobacterium tuberculosis) or human immunodeficiency virus (HIV) infection
Has known history of or is positive for hepatitis B or hepatitis C
Has received a live vaccine within 30 days prior to the first dose of study treatment
Has had radiotherapy within 14 days of randomization. Participants who received radiotherapy >14 days prior to randomization must have completely recovered from any radiotherapy-related AEs/toxicities

Sites / Locations

Kaiser Permanente Southern California ( Site 0003)
The University of Chicago Medical Center ( Site 0001)
University of Kansas ( Site 0029)
University of Maryland Medical Center ( Site 0013)
Dana Farber Cancer Center ( Site 0009)
Henry Ford Cancer Center ( Site 0018)
Washington University School of Medicine ( Site 0031)
Roswell Park Cancer Institute ( Site 0004)
Weill Cornell Medical College ( Site 0024)
University Hospitals Cleveland Medical Center ( Site 0002)
UPMC Cancer Center/Hillman Cancer Center ( Site 0015)
University of Tennessee Medical Center Knoxville ( Site 0017)
Centro de Investigaciones Clinicas - Clinica Viedma ( Site 0603)
Hospital Aleman ( Site 0605)
Hospital Municipal de Gastroenterologia Dr. Bonorino Udaondo ( Site 0602)
Sanatorio Allende - Cordoba ( Site 0604)
Hospital Privado Centro Medico Cordoba ( Site 0601)
Blacktown Hospital ( Site 2000)
Liverpool Hospital. ( Site 2001)
Princess Alexandra Hospital ( Site 2005)
Eastern Health ( Site 2002)
Peter MacCallum Cancer Centre ( Site 2003)
CETUS Hospital Dia Oncologia ( Site 0208)
Inst de Medicina Integral Professor Fernando Figueira- IMIP ( Site 0210)
Clinica de Hematologia e Oncologia Viver Ltda ( Site 0211)
Instituto Nacional do Cancer Jose Alencar Gomes da Silva INCA ( Site 0209)
Hospital Sao Vicente de Paulo ( Site 0204)
Uniao Brasileira de Educacao e Assistencia Hospital Sao Lucas da Pucrs ( Site 0201)
Fundacao Faculdade Regional de Medicina de Sao Jose do Rio Preto. ( Site 0203)
Hospital Alemao Oswaldo Cruz ( Site 0207)
Hospital de Clinicas de Porto Alegre ( Site 0200)
Instituto do Cancer de Sao Paulo - ICESP ( Site 0206)
Tom Baker Cancer Centre ( Site 0503)
Cross Cancer Institute ( Site 0502)
CancerCare Manitoba ( Site 0500)
Juravinski Cancer Center ( Site 0508)
The Ottawa Hospital - Cancer Care ( Site 0501)
Princess Margaret Cancer Centre ( Site 0505)
CISSS de la Monteregie-Centre ( Site 0504)
Jewish General Hospital ( Site 0507)
Hospital Regional de Concepcion Dr. Guillermo Grant Benavente ( Site 1003)
Pontificia Universidad Catolica de Chile ( Site 1001)
Hospital Clinico Universidad de Chile ( Site 1002)
Clinica Alemana de Temuco ( Site 1006)
Anhui Provincial Hospital ( Site 0106)
The First Affiliated Hospital of Anhui Medical University ( Site 0112)
Peking Union Medical College Hospital ( Site 0123)
The First Affiliated Hospital of Xiamen University ( Site 0119)
Guangdong General Hospital ( Site 0103)
The Affiliated Tumour Hospital of Harbin Medical University ( Site 0102)
Tongji Medical College Huazhong University of Science and Technology ( Site 0109)
Hunan Cancer Hospital ( Site 0105)
PLA Cancer Centre of Nanjing Bayi Hospital ( Site 0110)
Zhongda Hospital Southeast University ( Site 0125)
Jilin Cancer Hospital ( Site 0101)
The First Affiliated Hospital of Xi an Jiaotong University ( Site 0120)
Zhejiang Cancer Hospital ( Site 0116)
Beijing Cancer Hospital ( Site 0100)
Fujian Provincial Cancer Hospital ( Site 0104)
Shanghai Chest Hospital ( Site 0111)
Fudan University Shanghai Cancer Center ( Site 0108)
Renji Hospital Shanghai Jiaotong University School of Medicine ( Site 0114)
Henan Cancer Hospital ( Site 0107)
Rodrigo Botero SAS ( Site 2703)
Oncomedica S.A. ( Site 2701)
CIMCA Centro de Investigacion y Manejo del Cancer ( Site 2600)
Policlinico San Bosco ( Site 2602)
ICIMED - Instituto de Investigacion en Ciencias Medicas ( Site 2601)
Rigshospitalet ( Site 2301)
Odense Universitetshospital ( Site 2300)
Centre Leon Berard ( Site 0307)
CHU Brest - Institut de Cancerologie et d Hematologie ( Site 0305)
Centre Francois Baclesse ( Site 0310)
Centre Oscar Lambret ( Site 0304)
Institut du Cancer de Montpellier ( Site 0306)
CHU de Nantes - Hotel Dieu ( Site 0303)
Institut Mutualiste Montsouris ( Site 0300)
CHU de Saint Etienne Hopital Nord ( Site 0309)
Staedtisches Klinikum Dresden ( Site 1507)
Haematologisch-Onkologische Praxis Eppendorf Facharztzentrum Eppendorf - Hope ( Site 1502)
Universitaetsklinikum Leipzig ( Site 1501)
Klinikum Ludwigsburg ( Site 1509)
Universitatsklinikum Mannheim GmbH ( Site 1504)
Klinik fuer Haematologie. Onkologie und Gastroenterologie ( Site 1508)
III. Medizinische Klinik Klinikum rechts der Isar ( Site 1506)
Centro de Investigacion Oncologica ( Site 1402)
Oncomedica ( Site 1400)
Grupo Medico Angeles ( Site 1401)
Medi-K Cayala ( Site 1404)
Centro Regional de Sub Especialidades Medicas SA ( Site 1403)
Humanity Health Research Centre ( Site 1603)
Pamela Youde Nethersole Eastern Hospital ( Site 1601)
Princess Margaret Hospital. ( Site 1602)
Queen Mary Hospital ( Site 1600)
Aichi Cancer Center Hospital ( Site 0902)
National Cancer Center Hospital East ( Site 0908)
National Hospital Organization Shikoku Cancer Center ( Site 0901)
Hokkaido University Hospital ( Site 0916)
Hyogo Cancer Center ( Site 0913)
Kobe City Medical Center General Hospital ( Site 0929)
Ibaraki Prefectural Central Hospital ( Site 0918)
University of Tsukuba Hospital ( Site 0910)
Kagawa University Hospital ( Site 0915)
St. Marianna University School of Medicine Hospital ( Site 0903)
Kanagawa Cancer Center ( Site 0921)
Oita University Hospital ( Site 0930)
Kansai Medical University Hospital ( Site 0931)
Kindai University Hospital ( Site 0917)
Osaka University Hospital ( Site 0911)
Osaka Medical College Hospital ( Site 0925)
Saitama Cancer Center ( Site 0926)
Shizuoka Cancer Center Hospital and Research Institute ( Site 0914)
Kyorin University Hospital ( Site 0905)
Chiba University Hospital ( Site 0909)
Chiba Cancer Center ( Site 0900)
National Hospital Organization Kyushu Cancer Center ( Site 0906)
Kyushu University Hospital ( Site 0922)
Gifu University Hospital ( Site 0920)
Kumamoto University Hospital ( Site 0919)
Niigata Cancer Center Hospital ( Site 0924)
Osaka International Cancer Institute ( Site 0923)
Osaka General Medical Center ( Site 0912)
National Cancer Center Hospital ( Site 0907)
The Cancer Institute Hospital of JFCR ( Site 0904)
Keio University Hospital ( Site 0927)
National Cancer Center ( Site 1304)
Chonnam National University Hwasun Hospital ( Site 1305)
Seoul National University Cancer Hospital ( Site 1301)
Severance Hospital Yonsei University Health System ( Site 1302)
Asan Medical Center ( Site 1303)
Samsung Medical Center ( Site 1300)
Beacon International Specialist Centre ( Site 1803)
Hospital Kuala Lumpur ( Site 1805)
University Malaya Medical Centre ( Site 1802)
Instituto Regional de Enfermedades Neoplasicas del Sur IRENSUR ( Site 1702)
Hospital Nacional Guillermo Almenara Irigoyen ( Site 1701)
Instituto Nacional de Enfermedades Neoplasicas ( Site 1705)
S C Pelican Impex SRL ( Site 2403)
S.C. Radiotherapy Center Cluj S.R.L ( Site 2407)
S.C. Centrul de Oncologie Sf. Nectarie SRL ( Site 2404)
S.C.Focus Lab Plus S.R.L ( Site 2401)
S C Oncocenter Oncologie Medicala S R L ( Site 2405)
S.C.Gral Medical S.R.L ( Site 2406)
Spitalul Clinic Judetean De Urgenta Constanta ( Site 2402)
SBHCI RCOD of MHC RB ( Site 0407)
Leningrad Regional Oncology Center ( Site 0405)
National Medical and Surgical Center n.a. N.I.Pirogov ( Site 0402)
N.N. Blokhin NMRCO ( Site 0401)
Scientific Research Oncology Institute n.a. N.N.Petrov ( Site 0406)
St Petersburg City Clinical Oncology Dispensary ( Site 0409)
Tomsk Scientific Research Institute of Oncology ( Site 0403)
Cancer Care Langenhoven Drive Oncology Centre ( Site 2501)
The Medical Oncology Centre of Rosebank ( Site 2506)
WITS Clinical Research CMJAH Clinical Trial Site ( Site 2500)
The Oncology Centre ( Site 2502)
Cape Town Oncology Trials Pty Ltd ( Site 2508)
Outeniqua Cancercare Oncology Unit ( Site 2504)
Clinton Oncology Centre ( Site 2505)
Hospital Universitario Central de Asturias ( Site 0708)
Hosp. Gral. Universitari Germans Trias i Pujol ( Site 0701)
Hospital Universitari Vall d Hebron ( Site 0702)
Hospital Universitario Reina Sofia ( Site 0706)
Hospital Ramon y Cajal ( Site 0703)
Hospital Universitario La Paz ( Site 0700)
Complejo Hospitalario Virgen De La Victoria ( Site 0705)
Chang Gung Med Foundation. Kaohsiung Branch ( Site 1906)
Taipei Medical University Shuang Ho Hospital ( Site 1908)
China Medical University Hospital ( Site 1904)
Kuang Tien General Hospital ( Site 1909)
National Cheng Kung University Hospital ( Site 1905)
Chi Mei Medical Center Liuying ( Site 1907)
National Taiwan University Hospital ( Site 1900)
Koo Foundation Sun Yat-Sen Cancer Center ( Site 1902)
Chang Gung Medical Foundation. Linkou ( Site 1903)
Bumrungrad International Hospital ( Site 2203)
Chulalongkorn Hospital ( Site 2201)
Ramathibodi Hospital. ( Site 2202)
Phramongkutklao Hospital ( Site 2205)
Songklanagarind Hospital ( Site 2204)
Adana Sehir Hastanesi ( Site 0802)
Ankara Sehir Hastanesi ( Site 0808)
Istanbul Medeniyet Universitesi Goztepe EAH ( Site 0807)
Istanbul Universitesi Cerrahpasa Tip Fakultesi ( Site 0804)
Marmara Universitesi Pendik Egitim ve Arastirma Hastanesi ( Site 0801)
Medical Park Izmir Hastanesi ( Site 0800)
Inonu Universitesi Turgut Ozal Tip Merkezi ( Site 0803)
Lothian University Hospitals NHS Trust ( Site 1101)
St Luke's Cancer Centre ( Site 1102)
The Christie NHS Foundation Trust ( Site 1100)

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Pembrolizumab + SOC

Placebo + SOC

Arm Description

Participants receive pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) plus standard of care (SOC) chemotherapy with cisplatin 80 mg/m^2 IV Q3W and 5-FU 800 mg/m^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments will be administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle.

Participants receive placebo to pembrolizumab (saline) IV Q3W plus SOC chemotherapy with cisplatin 80 mg/m^2 IV Q3W and 5-FU 800 mg/m^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments will be administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle.

Outcomes

Primary Outcome Measures

Overall Survival (OS) in Participants With Esophageal Squamous Cell Carcinoma (ESCC) Whose Tumors Are Programmed Cell Death-Ligand 1 (PD-L1) Biomarker-Positive (Combined Positive Score [CPS] ≥10)

Overall survival was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS is reported here for all participants of the Intent-To-Treat (ITT) population (all randomized) who had ESCC and who were PD-L1 CPS ≥10.

OS in Participants With ESCC

OS in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)

Overall survival was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS is reported here for all participants of the ITT population (all randomized) who were PD-L1 CPS ≥10.

OS in All Participants

Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) As Assessed By Investigator in Participants With ESCC

PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 as assessed by the investigator, 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 had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS is reported here for all participants of the ITT population (all randomized) who had ESCC.

PFS Per RECIST 1.1 As Assessed By Investigator in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)

PFS Per RECIST 1.1 As Assessed By Investigator in All Participants

Secondary Outcome Measures

Objective Response Rate (ORR) Per RECIST 1.1 As Assessed By Investigator in All Participants

ORR was defined as the percentage of participants in the analysis population 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) per RECIST 1.1. as assessed by the investigator. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, the percentage of participants who experienced CR or PR is reported here as the ORR for all participants of the ITT population (all randomized).

ORR Per RECIST 1.1 As Assessed By Investigator in Participants With ESCC Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)

ORR Per RECIST 1.1 As Assessed By Investigator in Participants With ESCC

ORR Per RECIST 1.1 As Assessed By Investigator in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)

Duration of Response (DOR) Per RECIST 1.1 As Assessed By Investigator in All Participants

For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by the investigator, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death due to any cause, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Per protocol, DOR is reported here for all participants of the ITT population (all randomized) who had CR or PR.

DOR Per RECIST 1.1 As Assessed By Investigator in Participants With ESCC Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)

DOR Per RECIST 1.1 As Assessed By Investigator in Participants With ESCC

DOR Per RECIST 1.1 As Assessed By Investigator in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)

Number of Participants With an Adverse Event (AE)

An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did 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 that experienced at least one AE was reported for each treatment arm.

Number of Participants Discontinuing Study Treatment Due to an AE

An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did 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 that discontinued any study drug due to an AE was reported for each treatment arm.

Change From Baseline To Week 18 in the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Combined Score in All Participants

The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the Global Health Status (GHS) question "How would you rate your overall health during the past week?" (Item 29) and the Quality of Life (QoL) question "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores were standardized so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was reported by treatment arm as a pre-specified secondary analysis for all participants.

Change From Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score in Participants With ESCC Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)

Change From Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score in Participants With ESCC

Change From Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)

Change From Baseline in the EORTC Quality Of Life Questionnaire Oesophageal Module (QLQ-OES18) Subscale Scores in All Participants

The EORTC QLQ-OES18 is a disease-specific questionnaire developed and validated to address measurements specific to esophageal cancer and contains 18 items assessing symptoms of dysphagia, pain, reflux symptoms, eating restrictions, anxiety, dry mouth, taste, body image, and hair loss. For the purposes of this study, the Dysphagia subscale (three items), Pain subscale (three items), and Reflux subscale (two items) were evaluated. All subscale items were scored using a four-point Likert scale with the following response choices: 1=not at all, 2=a little, 3=quite a bit, 4=very much. Raw scores for the subscales were standardized into a range of 0 to 100 by linear transformation, with higher symptom scores represent a higher ("worse") level of symptoms. Per protocol, change from baseline to Week 18 in the Dysphagia, Pain, and Reflux subscales was reported for all participants in each treatment arm. Negative changes from baseline indicate a decrease in symptom severity.

Change From Baseline in the EORTC QLQ-OES18 Subscale Scores in Participants With ESCC Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)

The EORTC QLQ-OES18 is a disease-specific questionnaire developed and validated to address measurements specific to esophageal cancer and contains 18 items assessing symptoms of dysphagia, pain, reflux symptoms, eating restrictions, anxiety, dry mouth, taste, body image, and hair loss. For the purposes of this study, the Dysphagia subscale (three items), Pain subscale (three items), and Reflux subscale (two items) were evaluated. All subscale items were scored using a four-point Likert scale with the following response choices: 1=not at all, 2=a little, 3=quite a bit, 4=very much. Raw scores for the subscales were standardized into a range of 0 to 100 by linear transformation, with higher symptom scores representing a higher ("worse") level of symptoms. Change from baseline to Week 18 in the Dysphagia, Pain, and Reflux subscales was reported for participants with ESCC who were PD-L1 CPS≥10 in each treatment arm. Negative changes from baseline indicate a decrease in symptom severity.

Change From Baseline in the EORTC QLQ-OES18 Subscale Scores in Participants With ESCC

The EORTC QLQ-OES18 is a disease-specific questionnaire developed and validated to address measurements specific to esophageal cancer and contains 18 items assessing symptoms of dysphagia, pain, reflux symptoms, eating restrictions, anxiety, dry mouth, taste, body image, and hair loss. For the purposes of this study, the Dysphagia subscale (three items), Pain subscale (three items), and Reflux subscale (two items) were evaluated. All subscale items were scored using a four-point Likert scale with the following response choices: 1=not at all, 2=a little, 3=quite a bit, 4=very much. Raw scores for the subscales were standardized into a range of 0 to 100 by linear transformation, with higher symptom scores representing a higher ("worse") level of symptoms. Change from baseline to Week 18 in the Dysphagia, Pain, and Reflux subscales was reported for participants with ESCC in each treatment arm. Negative changes from baseline indicate a decrease in symptom severity.

Change From Baseline in the EORTC QLQ-OES18 Subscale Scores in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)

The EORTC QLQ-OES18 is a disease-specific questionnaire developed and validated to address measurements specific to esophageal cancer and contains 18 items assessing symptoms of dysphagia, pain, reflux symptoms, eating restrictions, anxiety, dry mouth, taste, body image, and hair loss. For the purposes of this study, the Dysphagia subscale (three items), Pain subscale (three items), and Reflux subscale (two items) were evaluated. All subscale items were scored using a four-point Likert scale with the following response choices: 1=not at all, 2=a little, 3=quite a bit, 4=very much. Raw scores for the subscales were standardized into a range of 0 to 100 by linear transformation, with higher symptom scores representing a higher ("worse") level of symptoms. Change from baseline to Week 18 in the Dysphagia, Pain, and Reflux subscales was reported for participants who were PD-L1 CPS≥10 in each treatment arm. Negative changes from baseline indicate a decrease in symptom severity.

Full Information

NCT ID

NCT03189719

First Posted

June 14, 2017

Last Updated

July 24, 2023

Sponsor

Merck Sharp & Dohme LLC

1. Study Identification

Unique Protocol Identification Number

NCT03189719

Brief Title

First-line Esophageal Carcinoma Study With Chemo vs. Chemo Plus Pembrolizumab (MK-3475-590/KEYNOTE-590)

Official Title

A Randomized, Double-Blind, Placebo-Controlled Phase III Clinical Trial of Pembrolizumab (MK-3475) in Combination With Cisplatin and 5-Fluorouracil Versus Placebo in Combination With Cisplatin and 5-Fluorouracil as First-Line Treatment in Subjects With Advanced/Metastatic Esophageal Carcinoma (KEYNOTE-590)

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Completed

Study Start Date

July 25, 2017 (Actual)

Primary Completion Date

July 2, 2020 (Actual)

Study Completion Date

July 10, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Merck Sharp & Dohme LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this trial is to evaluate efficacy and safety of pembrolizumab plus standard of care (SOC) chemotherapy with cisplatin and 5-fluorouracil (5-FU) versus placebo plus SOC chemotherapy with cisplatin and 5-FU as first-line treatment in participants with locally advanced or metastatic esophageal carcinoma. The overall primary efficacy hypotheses are as follows: In participants with esophageal squamous cell carcinoma (ESCC), participants whose tumors are programmed cell death-ligand 1 (PD-L1)-positive (defined as combined positive score [CPS] ≥10), ESCC participants whose tumors are PD-L1 positive (CPS ≥10), and in all participants, overall survival (OS) is superior with pembrolizumab plus SOC chemotherapy compared with placebo plus SOC chemotherapy. In participants with ESCC, participants whose tumors are PD-L1 positive (CPS ≥10), and in all participants, progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by investigator is superior with pembrolizumab plus SOC chemotherapy compared with placebo plus SOC chemotherapy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Esophageal Neoplasms

Keywords

Programmed Cell Death-1 (PD1, PD-1),, Programmed Cell Death Receptor Ligand 1 (PDL1, PD-L1), Programmed Cell Death Receptor Ligand 2 (PDL2, PD-L2)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

749 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Pembrolizumab + SOC

Arm Type

Experimental

Arm Description

Arm Title

Placebo + SOC

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Biological

Intervention Name(s)

Pembrolizumab

Other Intervention Name(s)

MK-3475

Intervention Description

200 mg administered IV Q3W on Day 1 of each 3-week cycle, up to 35 administrations.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo to pembrolizumab (saline) administered IV Q3W on Day 1 of each 3-week cycle, up to 35 administrations.

Intervention Type

Drug

Intervention Name(s)

Cisplatin

Intervention Description

80 mg/m^2 administered IV Q3W on Day 1 of each 3-week cycle. Duration of cisplatin treatment will be capped at 6 doses.

Intervention Type

Drug

Intervention Name(s)

5-FU

Intervention Description

800 mg/m^2/day (4000 mg/m^2 total per cycle) administered as continuous IV infusion on Days 1 to 5 (120 hours) of each 3-week cycle, or per local standard for 5-FU administration, up to 35 administrations.

Primary Outcome Measure Information:

Title

Overall Survival (OS) in Participants With Esophageal Squamous Cell Carcinoma (ESCC) Whose Tumors Are Programmed Cell Death-Ligand 1 (PD-L1) Biomarker-Positive (Combined Positive Score [CPS] ≥10)

Description

Time Frame