Efficacy Study of Nivolumab Plus Ipilimumab or Nivolumab Plus Chemotherapy Against Chemotherapy in Stomach Cancer or Stomach/Esophagus Junction Cancer (CheckMate649)

• ClinicalTrials.gov Identifier: NCT02872116
• Recruitment Status: Active, not recruiting
• First Posted: August 19, 2016
• Results First Posted: June 28, 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: August 16, 2016
• First Posted Date: August 19, 2016
• Results First Submitted Date: May 18, 2022
• Results First Posted Date: June 28, 2022
• Last Update Posted Date: December 4, 2023
• Actual Study Start Date: October 12, 2016
• Actual Primary Completion Date: May 27, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 23, 2022)

• Overall Survival (OS) in Participants Treated With Nivolumab Plus Chemotherapy vs Chemotherapy With PD-L1 CPS ≥ 5 [ Time Frame: From the date of randomization up to the date of death, up to approximately 17 months ]
  Overall survival (OS), defined as the time from randomization to the time of death, in participants treated with Nivolumab plus Chemotherapy vs Chemotherapy with PD-L1 CPS (combined positive score) ≥ 5. CPS is defined as the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100.
• Progression Free Survival (PFS) in Participants Treated With Nivolumab Plus Chemotherapy vs Chemotherapy With PD-L1 CPS ≥ 5 [ Time Frame: From randomization to the date of the first documented progressive disease (PD) per BICR or death due to any cause (up to approximately 10 months) ]
  Progression Free Survival (PFS) is defined as the time from randomization to the date of the first documented PD or death due to any cause. PD is determined by blinded independent committee review (BICR) per RECIST1.1 criteria in participants treated with Nivolumab plus Chemotherapy vs Chemotherapy with PD-L1 CPS ≥ 5. Progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking in reference the smallest sum on study that also demonstrated an absolute increase of at least 5 mm. CPS is defined as the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100.

• Original Primary Outcome Measures (submitted: August 18, 2016): Overall survival (OS) of nivolumab + ipilimumab versus oxaliplatin + fluoropyrimidine in subjects with programmed cell death ligand 1 (PD-L1) expressing tumors [ Time Frame: Approximately 35 months after the first patient is randomized ]

Current Secondary Outcome Measures (submitted: June 23, 2022)

• OS in Participants Treated With Nivolumab Plus Chemotherapy vs Chemotherapy [ Time Frame: From the date of randomization up to the date of death, up to approximately 17 months ]
  Overall survival (OS), defined as the time from randomization to the time of death, in participants treated with Nivolumab plus Chemotherapy vs Chemotherapy with PD-L1 CPS ≥ 1, 10, and all randomized participants. CPS is defined as the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100.
• PFS in Participants Treated With Nivolumab Plus Chemotherapy vs Chemotherapy [ Time Frame: From randomization to the date of the first documented progressive disease (PD) per BICR or death due to any cause (up to approximately 10 months) ]
  Progression free survival (PFS), defined as the time from randomization to the date of the first documented progressive disease (PD) or death due to any cause, in participants treated with Nivolumab plus Chemotherapy vs Chemotherapy by BICR per RECIST1.1 in participants with PD-L1 CPS ≥ 10, 1, or all randomized subjects. Progreessive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking in reference the smallest sum on study that also demonstrated an absolute increase of at least 5 mm. CPS is defined as the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100.
• Objective Response Rate [ Time Frame: From randomization to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (up to approximately 43 months) ]
  Objective response rate (ORR) as assessed by BICR in participants with PD-L1 CPS ≥ 10, 5, 1, or all randomized participants. ORR is a percentage of participants determined by the number of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of measurable participants with target lesion at baseline. BOR is defined as the best response designation as determined by the BICR, recorded between the date of randomization and the date of objectively documented progression (per RECIST 1.1 as determined by the BICR) or the date of subsequent anti-cancer therapy, whichever occurs first. CR is defined as the disappearance of all target lesions. PR is define as at 30% decrease in the sum of diameters of target lesions. The 806 chemotherapy treated participants are split into two separate arms (Arm 2a and Arm 2b) to act as comparison groups to the other treatment arms.
• OS in Participants Treated With Nivolumab Plus Ipilimumab vs Chemotherapy [ Time Frame: From the date of randomization up to the date of death, up to approximately 14 months ]
  Overall survival (OS), defined as the time from randomization to the time of death, in participants treated with Nivolumab plus Ipilimumab vs Chemotherapy with PD-L1 CPS (combined positive score) ≥ 1, 5, 10, and all randomized participants. CPS is defined as the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100.
• Time to Symptom Deterioration (TTSD) [ Time Frame: From randomization until a clinically meaningful decline from baseline in GaCS score ]
  TTSD is defined as the the time from randomization until a clinically meaningful decline from baseline in Gastric Cancer Subscale (GaCS) score. A clinically meaningful deterioration is defined as a reduction of 8.2 points in the GaCS score. Subjects who do not deteriorate will be censored at the time of their last GACS assessment. Subjects without baseline GaCS assessment will be censored on the randomization date. Those with baseline GaCS, who do not have any GaCS assessments after randomization will be censored on the day after randomization.
• PFS in Participants Treated With Nivolumab Plus Ipilimumab vs Chemotherapy [ Time Frame: From randomization to the date of the first documented progressive disease (PD) per BICR or death due to any cause (up to approximately 9 months) ]
  Progression Free Survival (PFS) is defined as the time from randomization to the date of the first documented PD or death due to any cause. PD is determined by blinded independent committee review (BICR) per RECIST1.1 criteria in participants treated with Nivolumab plus Ipilumab vs Chemotherapy with PD-L1 CPS ≥ 10, 5, 1 or all randomized participants. Progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking in reference the smallest sum on study that also demonstrated an absolute increase of at least 5 mm. CPS is defined as the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100.

Original Secondary Outcome Measures (submitted: August 18, 2016)

• OS of nivolumab + ipilimumab versus oxaliplatin + fluoropyrimidine in all randomized subjects [ Time Frame: Approximately 35 months after the first patient is randomized ]
• Progression-free Survival (PFS) of nivolumab + ipilimumab versus oxaliplatin + fluoropyrimidine in subjects with PD-L1 expressing tumors and all randomized subjects [ Time Frame: Approximately 35 months after the first patient is randomized ]
• Time to Symptom Deterioration (TTSD) assessed with Gastric Cancer Subscale (GaCS) questionnaire in subjects with PD-L1 expressing tumors and all randomized subjects [ Time Frame: Approximately 35 months after the first patient is randomized ]

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

Descriptive Information

• Brief Title: Efficacy Study of Nivolumab Plus Ipilimumab or Nivolumab Plus Chemotherapy Against Chemotherapy in Stomach Cancer or Stomach/Esophagus Junction Cancer
• Official Title: A Randomized, Multicenter, Open-Label, Phase 3 Study of Nivolumab Plus Ipilimumab or Nivolumab in Combination With Oxaliplatin Plus Fluoropyrimidine Versus Oxaliplatin Plus Fluoropyrimidine in Subjects With Previously Untreated Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer
• Brief Summary: The main purpose of this study is to compare how long patients with gastric or gastroesophageal junction cancer live after receiving nivolumab and ipilimumab or nivolumab and chemotherapy compared with patients receiving chemotherapy alone.
• 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

• Gastric Cancer
• Gastroesophageal Junction Cancer
• Esophageal Adenocarcinoma

Intervention

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

  • Opdivo
  • BMS-936558
• Drug: Ipilimumab
  Specified dose on specified days
  Other Names:

  • Yervoy
  • BMS-734016
• Drug: Oxaliplatin
  Specified dose on specified days
• Drug: Capecitabine
  Specified dose on specified days
• Drug: Leucovorin
  Specified dose on specified days
• Drug: Fluorouracil
  Specified dose on specified days

Study Arms

• Experimental: Nivolumab + Ipilimumab

  Nivolumab + Ipilimumab for 4 doses, followed by Nivolumab monotherapy

  Enrollment is closed for this arm

  Interventions:

  • Drug: Nivolumab
  • Drug: Ipilimumab
• Active Comparator: XELOX (Oxaliplatin + Capecitabine)
  Interventions:

  • Drug: Oxaliplatin
  • Drug: Capecitabine
• Active Comparator: FOLFOX (Oxaliplatin + Leucovorin + Fluorouracil)
  Interventions:

  • Drug: Oxaliplatin
  • Drug: Leucovorin
  • Drug: Fluorouracil
• Experimental: Nivolumab + XELOX
  Interventions:

  • Drug: Nivolumab
  • Drug: Oxaliplatin
  • Drug: Capecitabine
• Experimental: Nivolumab + FOLFOX
  Interventions:

  • Drug: Nivolumab
  • Drug: Oxaliplatin
  • Drug: Leucovorin
  • Drug: Fluorouracil

• Publications *: Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. doi: 10.1016/S0140-6736(21)00797-2. Epub 2021 Jun 5.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: May 19, 2021): 2031
• Original Estimated Enrollment (submitted: August 18, 2016): 750
• Estimated Study Completion Date: May 31, 2024
• Actual Primary Completion Date: May 27, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Male or Female at least 18 years of age
• Must have gastric cancer or gastroesophageal junction cancer that cannot be operated on and that is advanced or has spread out
• Did not receive neoadjuvant or adjuvant treatment (chemotherapy, radiotherapy, or both) for their disease within the last 6 months
• 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 that have not been treated
• 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

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, Brazil, Canada, Chile, China, Colombia, Czechia, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Japan, Korea, Republic of, Mexico, Peru, Poland, Portugal, Romania, Russian Federation, Singapore, Spain, Taiwan, Turkey, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT02872116
• Other Study ID Numbers: CA209-649; 2016-001018-76 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

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