A Study to Evaluate Efficacy in Subjects With Esophageal Cancer Treated With Nivolumab and Ipilimumab or Nivolumab Combined With Fluorouracil Plus Cisplatin Versus Fluorouracil Plus Cisplatin (CheckMate 648)

• ClinicalTrials.gov Identifier: NCT03143153
• Recruitment Status: Active, not recruiting
• First Posted: May 8, 2017
• Results First Posted: March 2, 2022
• Last Update Posted: December 4, 2023
• Sponsor: Bristol-Myers Squibb
• Collaborator: Ono Pharmaceutical Co. Ltd
• Information provided by (Responsible Party): Bristol-Myers Squibb

Tracking Information

• First Submitted Date: May 4, 2017
• First Posted Date: May 8, 2017
• Results First Submitted Date: January 11, 2022
• Results First Posted Date: March 2, 2022
• Last Update Posted Date: December 4, 2023
• Actual Study Start Date: June 29, 2017
• Actual Primary Completion Date: January 18, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 11, 2022)

• Overall Survival (OS) in Participants With Tumor Cell PD-L1 [ Time Frame: From the date of randomization to up to the date of death (up to approximately 20 months) ]
  Overall Survival (OS) is defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS will be censored on the last date the subject was known to be alive.
• Progression-free Survival (PFS) as Assessed by BICR in Participants With Tumor Cell PD-L1 [ Time Frame: From the date of randomization to up to the date of the first documented disease progression or death (up to approximately 9 months) ]
  Progression-free survival (PFS) is defined as the time from randomization to the date of the first documented progressive disease (PD) per Blinded Independent Central Review (BICR) or death due to any cause. Participants who die without a reported prior PD per BICR (and die without start of subsequent therapy) will be considered to have progressed on the date of death. Participants who did not have documented PD per BICR per RECIST1.1 criteria and who did not die, will be censored at the date of the last evaluable tumor assessment on or prior to initiation of the subsequent anti-cancer therapy. Participants who did not have any on-study tumor assessments and did not die (or died after initiation of the subsequent anti-cancer therapy) will be censored at the randomization date. Participants who started any subsequent anti-cancer therapy without a prior reported PD per BICR will be censored at the last tumor assessment on or prior to initiation of the subsequent anti-cancer therapy.

Original Primary Outcome Measures (submitted: May 4, 2017)

• Overall survival (OS) [ Time Frame: Approximately 49 months from time first pstient is randomized ]
  In subjects with PD-L1 expressing tumors
• Progression-free Survival (PFS) [ Time Frame: Approximately 33 months from time first patient is randomized ]
  As assessed by blinded independent central review committee (BICR) in subjects with PD-L1 expressing tumors

Current Secondary Outcome Measures (submitted: January 11, 2022)

• Overall Survival (OS) in All Randomized Participants [ Time Frame: From the date of randomization to up to the date of death (up to approximately 16 months) ]
  Overall Survival (OS) is defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS will be censored on the last date the subject was known to be alive.
• Progression-free Survival (PFS) in All Randomized Participants as Assessed by BICR [ Time Frame: From the date of randomization to up to the date of the first documented disease progression or death (up to approximately 7 months) ]
  Progression-free survival (PFS) is defined as the time from randomization to the date of the first documented progressive disease (PD) per Blinded Independent Central Review (BICR) or death due to any cause. Participants who die without a reported prior PD per BICR (and die without start of subsequent therapy) will be considered to have progressed on the date of death. Participants who did not have documented PD per BICR per RECIST1.1 criteria and who did not die, will be censored at the date of the last evaluable tumor assessment on or prior to initiation of the subsequent anti-cancer therapy. Participants who did not have any on-study tumor assessments and did not die (or died after initiation of the subsequent anti-cancer therapy) will be censored at the randomization date. Participants who started any subsequent anti-cancer therapy without a prior reported PD per BICR will be censored at the last tumor assessment on or prior to initiation of the subsequent anti-cancer therapy.
• Objective Response Rate (ORR) as Assessed by BICR [ Time Frame: From the date of randomization to up to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (up to 40 months) ]
  Objective response rate (ORR) is defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). Best overall response (BOR) is defined as the best response designation as determined by BICR, recorded between the date of randomization and the date of objectively documented progression (per RECIST 1.1) or the date of subsequent anti-cancer therapy (including tumor-directed radiotherapy and tumor-directed surgery), whichever occurs first. Partial response is defined as at least a 30% decrease in the sum of diameters of target lesions. Complete response is defined as the disappearance of all target lesions and the reduction of any pathological lymph nodes to <10 mm.

Original Secondary Outcome Measures (submitted: May 4, 2017)

• Overall survival (OS) [ Time Frame: Approximately 49 months from time first patient is randomized ]
  In All Randomized subjects
• Progression-free Survival (PFS) [ Time Frame: Approximately 33 months from time first patient is randomized ]
  As assessed by BICR in All Randomized subjects
• Objective Response Rate (ORR) [ Time Frame: Approximately 33 months from time first patient is randomized ]
  As assessed by BICR in subjects with PD-L1 expressing tumors and All Randomized subjects

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Evaluate Efficacy in Subjects With Esophageal Cancer Treated With Nivolumab and Ipilimumab or Nivolumab Combined With Fluorouracil Plus Cisplatin Versus Fluorouracil Plus Cisplatin
• Official Title: A Randomized Phase 3 Study of Nivolumab Plus Ipilimumab or Nivolumab Combined With Fluorouracil Plus Cisplatin Versus Fluorouracil Plus Cisplatin in Subjects With Unresectable Advanced, Recurrent or Metastatic Previously Untreated Esophageal Squamous Cell Carcinoma
• Brief Summary: The main purpose of this study is to compare how long subjects with esophageal cancer live overall or live without disease progression after receiving nivolumab and ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus cisplatin
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Various Advanced Cancer

Intervention

• Biological: Nivolumab
  Specified dose on specified days
  Other Names:

  • BMS-936558 (Nivolumab)
  • Opdivo (Nivolumab)
• Biological: Ipilimumab
  Specified dose on specified days
  Other Names:

  • BMS-734016 (Ipilimumab)
  • Yervoy (Ipilimumab)
• Drug: Cisplatin
  Specified dose on specified days
• Drug: Fluorouracil
  Specified dose on specified days

Study Arms

• Experimental: Nivolumab + Ipilimumab
  Interventions:

  • Biological: Nivolumab
  • Biological: Ipilimumab
• Experimental: Nivolumab + Cisplatin + Fluorouacil
  Interventions:

  • Biological: Nivolumab
  • Drug: Cisplatin
  • Drug: Fluorouracil
• Active Comparator: Cisplatin + Fluorouracil
  Interventions:

  • Drug: Cisplatin
  • Drug: Fluorouracil

Publications *

• Kato K, Doki Y, Ogata T, Motoyama S, Kawakami H, Ueno M, Kojima T, Shirakawa Y, Okada M, Ishihara R, Kubota Y, Amaya-Chanaga C, Chen T, Matsumura Y, Kitagawa Y. First-line nivolumab plus ipilimumab or chemotherapy versus chemotherapy alone in advanced esophageal squamous cell carcinoma: a Japanese subgroup analysis of open-label, phase 3 trial (CheckMate 648/ONO-4538-50). Esophagus. 2023 Apr;20(2):291-301. doi: 10.1007/s10388-022-00970-1. Epub 2022 Nov 19.
• Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Ostoich SA, Kim HR, Ueno M, Mansoor W, Yang WC, Liu T, Bridgewater J, Makino T, Xynos I, Liu X, Lei M, Kondo K, Patel A, Gricar J, Chau I, Kitagawa Y; CheckMate 648 Trial Investigators. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med. 2022 Feb 3;386(5):449-462. doi: 10.1056/NEJMoa2111380.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: May 5, 2021): 970
• Original Estimated Enrollment (submitted: May 4, 2017): 939
• Estimated Study Completion Date: January 13, 2025
• Actual Primary Completion Date: January 18, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Must have histologically confirmed squamous cell carcinoma or adenosquamous cell carcinoma of esophagus
• Male or Female at least 18 years of age
• Must have esophageal cancer that cannot be operated on, or treated with definitive chemoradiation with curative intent, that is advanced, reoccurring or has spread out
• Must have full activity or, if limited, must be able to walk and carry out light activities such as light house work or office work
• Must agree to provide tumor tissue sample, either from a previous surgery or biopsy within 6 months or fresh, prior to the start of treatment in this study

Exclusion Criteria

• Presence of tumor cells in the brain or spinal cord which are symptomatic or require treatment
• Active known or suspected autoimmune disease
• Any serious or uncontrolled medical disorder or active infection
• Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Any positive test result for hepatitis B or C indicating acute or chronic infection and/or detectable virus

Other protocol defined inclusion/exclusion criteria apply

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Brazil, Canada, Chile, China, Colombia, Czechia, Denmark, France, Hong Kong, Italy, Japan, Korea, Republic of, Mexico, Peru, Poland, Portugal, Romania, Russian Federation, Singapore, Spain, Taiwan, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT03143153
• Other Study ID Numbers: CA209-648; 2016-001514-20 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Bristol-Myers Squibb
• Original Responsible Party: Same as current
• Current Study Sponsor: Bristol-Myers Squibb
• Original Study Sponsor: Same as current
• Collaborators: Ono Pharmaceutical Co. Ltd

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

• PRS Account: Bristol-Myers Squibb
• Verification Date: November 2023