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

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ClinicalTrials.gov Identifier: NCT03881111
Recruitment Status : Recruiting
First Posted : March 19, 2019
Last Update Posted : March 19, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:

The purpose of this Chinese extension study is to evaluate efficacy and safety of pembrolizumab plus cisplatin and 5-fluorouracil (5-FU) chemotherapy versus placebo plus cisplatin and 5-FU chemotherapy as first-line treatment in a Chinese cohort of participants with locally advanced or metastatic esophageal carcinoma.

The primary efficacy hypotheses are that both progression-free survival (PFS), according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and determined by blinded independent central review, and overall survival (OS) are superior with pembrolizumab plus chemotherapy compared with placebo plus chemotherapy in all Chinese participants as well as Chinese participants whose tumors are programmed cell death-ligand 1 (PD-L1)-positive.


Condition or disease Intervention/treatment Phase
Esophageal Neoplasms Biological: Pembrolizumab Drug: Placebo Drug: Cisplatin Drug: 5-FU Phase 3

Detailed Description:
The Chinese extension to MK-3475-590 (NCT03189719) will enroll a total of approximately 90 participants.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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)
Actual Study Start Date : January 21, 2019
Estimated Primary Completion Date : May 11, 2021
Estimated Study Completion Date : May 11, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Pembrolizumab + Cisplatin + 5-FU
Participants receive pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W), 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). All treatments will be administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle.
Biological: Pembrolizumab
200 mg administered IV Q3W on Day 1 of each 3-week cycle, up to 35 administrations.
Other Name: MK-3475

Drug: Cisplatin
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.

Drug: 5-FU
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.

Placebo Comparator: Placebo + Cisplatin + 5-FU
Participants receive placebo to pembrolizumab (saline) IV Q3W, 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). All treatments will be administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle.
Drug: Placebo
Placebo to pembrolizumab (saline) administered IV Q3W on Day 1 of each 3-week cycle, up to 35 administrations.

Drug: Cisplatin
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.

Drug: 5-FU
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.




Primary Outcome Measures :
  1. Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 in all participants [ Time Frame: Up to 2 years ]
    PFS is defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on blinded independent central review or death due to any cause, whichever occurs first. For this analysis, PFS will be assessed in all participants.

  2. PFS per RECIST Version 1.1 in PD-L1 biomarker-positive participants [ Time Frame: Up to 2 years ]
    PFS is defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on blinded independent central review or death due to any cause, whichever occurs first. For this analysis, PFS will be assessed in PD-L1 biomarker-positive participants.

  3. Overall Survival (OS) in all participants [ Time Frame: Up to 2 years ]
    OS is defined as the time from randomization to death due to any cause. For this analysis, OS will be assessed in all participants.

  4. OS in PD-L1 biomarker-positive participants [ Time Frame: Up to 2 years ]
    OS is defined as the time from randomization to death due to any cause. For this analysis, OS will be assessed in PD-L1 biomarker-positive participants.


Secondary Outcome Measures :
  1. Objective Response Rate (ORR) per RECIST 1.1 in all participants [ Time Frame: Up to 2 years ]
    ORR is defined as the percentage of participants in the analysis population who have 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. For this analysis, ORR will be assessed in all participants.

  2. ORR per RECIST 1.1 in PD-L1 biomarker-positive participants [ Time Frame: Up to 2 years ]
    ORR is defined as the percentage of participants in the analysis population who have 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. For this analysis, ORR will be assessed in PD-L1 biomarker-positive participants.

  3. Duration of Response (DOR) per RECIST 1.1 in all participants [ Time Frame: Up to 2 years ]
    For participants who demonstrate CR (disappearance of all target lesions) or PR (≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters), DOR is defined as the time from first documented evidence of CR or PR until disease progression per RECIST 1.1 based on assessments by blinded independent central review or death due to any cause, whichever occurs first. For this analysis, DOR will be assessed in all participants.

  4. DOR per RECIST 1.1 in PD-L1 biomarker-positive participants [ Time Frame: Up to 2 years ]
    For participants who demonstrate CR (disappearance of all target lesions) or PR (≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters), DOR is defined as the time from first documented evidence of CR or PR until disease progression per RECIST 1.1 based on assessments by blinded independent central review or death due to any cause, whichever occurs first. For this analysis, DOR will be assessed in PD-L1 biomarker-positive participants.

  5. Number of participants with an adverse event (AE) [ Time Frame: Up to 27 months ]
    An AE is 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 can 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 preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.

  6. Number of participants discontinuing study treatment due to an AE [ Time Frame: Up to 2 years ]
    An AE is 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 can 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 preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.

  7. Change from baseline in the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) Score [ Time Frame: Baseline, End of Treatment (~1 year) ]
    The EORTC QLQ-C30 was developed to assess the quality of life of patients with cancer. It contains 30 questions (items), 24 of which aggregate into nine multi-item scales representing various aspects, or dimensions, of quality of life (QOL): one global scale, five functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, nausea, pain), and six additional single-symptom items assessing additional symptoms commonly reported by cancer patients (dyspnoea, loss of appetite, insomnia, constipation and diarrhoea) and perceived financial impact of the disease. Individual items are scored on a 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Raw scores for each scale are standardized into a range of 0 to 100 by linear transformation; a higher score on the global and functional scales represents a higher ("better") level of functioning, and a higher score on the symptom scale represents a higher ("worse") level of symptoms.

  8. Change from baseline in the EORTC Quality Of Life Questionnaire Oesophageal Module (QLQ-OES18) Score [ Time Frame: Baseline, End of Treatment (~1 year) ]
    The EORTC QLQ-OES18 is a disease-specific questionnaire developed and validated to address measurements specific to esophageal cancer. It contains 18 items and is based on four subscales—dysphagia (three items), eating (four items), reflux (two items) and pain (three items), as well as six single-item subscales—saliva swallowing, choking, dry mouth, taste, cough and speech. All items are scored using a four-point Likert scale that offers these response choices: 1=not at all, 2=a little, 3=quite a bit, 4=very much. Raw scores are standardized into a range of 0 to 100 by linear transformation; higher symptom scores represent a higher ("worse") level of symptoms.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

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

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 ClinicalTrials.gov identifier (NCT number): NCT03881111


Contacts
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Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com

Locations
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China, Anhui
Anhui Provincial Hospital ( Site 0106) Recruiting
Hefei, Anhui, China, 230036
Contact: Study Coordinator    +8655162283524      
The First Affiliated Hospital of Anhui Medical University ( Site 0112) Recruiting
Hefei, Anhui, China, 230088
Contact: Study Coordinator    +8613805692145      
China, Beijing
Peking Union Medical College Hospital ( Site 0123) Recruiting
Beijing, Beijing, China, 100032
Contact: Study Coordinator    +8613511071908      
China, Fujian
The First Affiliated Hospital of Xiamen University ( Site 0119) Recruiting
Xiamen, Fujian, China, 361000
Contact: Study Coordinator    +8613860458889      
China, Guangdong
Guangdong General Hospital ( Site 0103) Recruiting
Guangzhou, Guangdong, China, 510120
Contact: Study Coordinator    +8613332888281      
China, Heilongjiang
The Affiliated Tumour Hospital of Harbin Medical University ( Site 0102) Recruiting
Harbin, Heilongjiang, China, 150081
Contact: Study Coordinator    +8645186298303      
China, Hunan
Hunan Cancer Hospital ( Site 0105) Recruiting
Changsha, Hunan, China, 410013
Contact: Study Coordinator    +8613319602869      
China, Jiangsu
PLA Cancer Centre of Nanjing Bayi Hospital ( Site 0110) Recruiting
Nanjing, Jiangsu, China, 210002
Contact: Study Coordinator    +862584453932      
Jiangsu Cancer Hospital ( Site 0117) Recruiting
Nanjing, Jiangsu, China, 210009
Contact: Study Coordinator    +8602583283364      
Zhongda Hospital Southeast University ( Site 0125) Recruiting
Nanjing, Jiangsu, China, 210009
Contact: Study Coordinator    +862583272338      
China, Jilin
Jilin Cancer Hospital ( Site 0101) Recruiting
Changchun, Jilin, China, 130012
Contact: Study Coordinator    +8643185872688      
China, Shannxi
The First Affiliated Hospital of Xi an Jiaotong University ( Site 0120) Recruiting
Xi'an, Shannxi, China, 710061
Contact: Study Coordinator    +8602985324600      
China, Zhejiang
Zhejiang Cancer Hospital ( Site 0116) Recruiting
Hangzhou, Zhejiang, China, 310022
Contact: Study Coordinator    +8657188122222      
China
Beijing Cancer Hospital ( Site 0100) Recruiting
Beijing, China, 100142
Contact: Study Coordinator    +861088140650      
Fujian Provincial Cancer Hospital ( Site 0104) Recruiting
Fuzhou, China, 350014
Contact: Study Coordinator    +8613809500871      
Shanghai Chest Hospital ( Site 0111) Recruiting
Shanghai, China, 200030
Contact: Study Coordinator    2122200000      
Fudan University Shanghai Cancer Center ( Site 0108) Recruiting
Shanghai, China, 200032
Contact: Study Coordinator    +8613641980099      
Renji Hospital Shanghai Jiaotong University School of Medicine ( Site 0114) Recruiting
Shanghai, China, 200127
Contact: Study Coordinator    +8613761254228      
Tongji Medical College Huazhong University of Science and Technology ( Site 0109) Recruiting
Wuhan, China, 430030
Contact: Study Coordinator    +862783662688      
Henan Cancer Hospital ( Site 0107) Recruiting
Zhengzhou, China, 450008
Contact: Study Coordinator    +8618638553211      
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.

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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT03881111     History of Changes
Other Study ID Numbers: 3475-590 China Extension
2017-000958-19 ( EudraCT Number )
173739 ( Registry Identifier: JAPIC-CTI )
MK-3475-590 ( Other Identifier: Merck Protocol Number )
KEYNOTE-590 ( Other Identifier: Merck )
First Posted: March 19, 2019    Key Record Dates
Last Update Posted: March 19, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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

Additional relevant MeSH terms:
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Esophageal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Cisplatin
Pembrolizumab
Antineoplastic Agents
Antineoplastic Agents, Immunological