Study of Nivolumab (BMS-936558) Compared With Dacarbazine in Untreated, Unresectable, or Metastatic Melanoma (CheckMate 066)

• ClinicalTrials.gov Identifier: NCT01721772
• Recruitment Status: Completed
• First Posted: November 6, 2012
• Results First Posted: February 25, 2016
• Last Update Posted: July 12, 2022
• Sponsor: Bristol-Myers Squibb
• Information provided by (Responsible Party): Bristol-Myers Squibb

Tracking Information

• First Submitted Date: November 2, 2012
• First Posted Date: November 6, 2012
• Results First Submitted Date: November 20, 2015
• Results First Posted Date: February 25, 2016
• Last Update Posted Date: July 12, 2022
• Actual Study Start Date: January 18, 2013
• Actual Primary Completion Date: June 24, 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 17, 2022)

• Overall Survival (OS) [ Time Frame: From date of randomization to date of death. For those without documentation of death, to the last date the participant was known to be alive, assessed up to 17 months. ]
  OS is defined as the time between the date of randomization and the date of death or the last date the participant was known to be alive.
• Overall Survival (OS) Rate [ Time Frame: From randomization to 6 months and or to 12 months ]
  OS rate is calculated as the percentage of participants alive at the indicated timepoints

Original Primary Outcome Measures (submitted: November 2, 2012)

Endpoint of Overall survival (OS) [ Time Frame: Up to 5 years ]

OS is defined as the time between the date of randomization and the date of death. For subjects without documentation of death, OS will be censored on the last date the subject was known to be alive

Current Secondary Outcome Measures (submitted: June 17, 2022)

• Progression-free Survival (PFS) [ Time Frame: From date of randomization up to date of disease progression or death, up to approximately 84 months ]
  Investigator-assessed PFS is defined as the time from randomization to the date of the first documented progression, as determined by the investigator, or death due to any cause, whichever occurs first. Patients who died without progressing were considered to have progressed on the date of their death. Those who did not progress or die were documented on the date of their last evaluable tumor assessment. Patients who did not have any on-study tumor assessments and did not die were documented on their date of randomization. Those who started any subsequent anticancer therapy without a prior reported progression were documented on the date of their last evaluable tumor assessment prior to initiation of subsequent anticancer therapy.
• Progression-free Survival (PFS) Rate [ Time Frame: From randomization to the specified timepoints, up to 84 months ]
  The PFS rate at a time point is the estimated percentage of patients who have not progressed and are alive at that time point following randomization and is estimated using the Kaplan-Meier methodology.
• Objective Response Rate (ORR) [ Time Frame: Tumor assessments beginning at 9 weeks following randomization and continuing every 6 weeks for the first year, then every 12 weeks thereafter until disease progression or death, assessed to 94 months ]
  ORR is defined as the percentage of participants with a best overall response of Response Evaluation Criteria in Solid Tumors (RECIST) defined complete response (CR) or partial response (PR). RECIST, volume 1.1 for target lesions: CR=disappearance of all target lesions; PR=at least a 30% decrease in the sum of the longest dimension (LD) of target lesions, taking as reference the baseline sum LD; stable disease=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum LD since the treatment started; PD=at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions, and the sum LD must have an absolute increase of ≥5 mm.
• Overall Survival by Programmed Cell Death Ligand 1 (PD-L1) Expression Level [ Time Frame: From date of randomization to date of disease progression or death, up to approximately 94 months ]
  Overall Survival is defined as the time between the date of randomization and the date of death or the last date the participant was known to be alive. PD-L1 expression level is defined as the percent of tumor cells demonstrating plasma membrane PD-L1-staining in a minimum of 100 evaluable tumor cells per a Dako PD-L1 IHC (immunohistochemistry) assay (referred to as quantifiable PD-L1 expression). Assessment of OS by PD-L1 expression as measured by a validated assay and comparing OS in patients with tumor PD-L1 expression ≥5% (PD-L1 positive) versus patients with tumor PD-L1 expression <5% (PD-L1 negative). Tumor tissue samples for PD-L1 testing were collected at screening from metastatic or unresectable sites prior to randomization.
• Change From Baseline in Health-related Quality of Life (HRQoL) Scores [ Time Frame: At baseline and every 6 weeks for 12 months and at follow-up visits 1 and 2, assessed up to 93 months ]
  HRQoL is evaluated by mean changes from baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) global health status/quality of life composite scale in all randomized patients. The QLQ-30 is a cancer-specific, self-administered questionnaire that contains 30 questions, covering global, functional, and symptom scales. Scores range from 0 to 100. Higher scores on global and functional scales indicate better quality of life (QoL), while higher scores on the symptom scales indicate declining QoL.

Original Secondary Outcome Measures (submitted: November 2, 2012)

• Progression-free survival (PFS) [ Time Frame: Up to 5 years ]
  PFS is defined as the time from randomization to the date of the first documented progression, as determined by the investigator, or death due to any cause, whichever occurs first
• Objective Response Rate (ORR) [ Time Frame: Up to 5 years ]
  ORR is defined as the number of subjects with a Best Overall Response (BOR) of Complete Response (CR) or Partial response (PR) divided by the number of randomized subjects for each treatment arm
• Programmed death-ligand 1 (PD-L1) expression as predictive biomarker [ Time Frame: Up to 5 years ]
  PD-L1 expression as measured by the endpoint OS based on PD-L1 expression level
• Health Related Quality of Life (HRQoL) [ Time Frame: Up to 5 years ]
  HRQoL as measured by mean changes from baseline in the EORTC-QLQ-C30 global health status/QoL composite scale and by mean changes from baseline in the remaining EORTC QLQ-C30 scales in all randomized subjects; EORTC-QLQ-C30 = European Organisation for Research and Treatment of Cancer - Quality of Life Questionnaire - Core 30

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

Descriptive Information

• Brief Title: Study of Nivolumab (BMS-936558) Compared With Dacarbazine in Untreated, Unresectable, or Metastatic Melanoma
• Official Title: A Phase 3, Randomized, Double-Blind Study of BMS-936558 vs Dacarbazine in Subjects With Previously Untreated, Unresectable or Metastatic Melanoma
• Brief Summary: The purpose of this study is to compare the clinical benefit, as measured by overall survival, of nivolumab with that of. dacarbazine in patients with previously untreated, unresectable, or metastatic melanoma
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Melanoma

Intervention

• Biological: BMS-936558 (Nivolumab)
• Biological: Placebo matching BMS-936558 (Nivolumab)
• Drug: Dacarbazine
• Drug: Placebo matching Dacarbazine

Study Arms

• Experimental: Nivolumab, 3 mg/kg
  Participants received nivolumab, 3 mg/kg, solution administered Intravenously (IV) every 2 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion. Eligible participants may switch to nivolumab at 480mg every 4 weeks until documented disease progression, discontinuation, withdrawal of consent or the study ends.
  Interventions:

  • Biological: BMS-936558 (Nivolumab)
  • Drug: Placebo matching Dacarbazine
• Active Comparator: Dacarbazine, 1000 mg/m^2
  Participants received dacarbazine, 1000 mg/m^2, solution administered IV every 3 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion. Eligible participants may cross-over to nivolumab open label treatment, either 3 mg/kg every 2 weeks or 480mg every 4 weeks until documented disease progression, discontinuation, withdrawal of consent or the study ends.
  Interventions:

  • Biological: Placebo matching BMS-936558 (Nivolumab)
  • Drug: Dacarbazine

Publications *

• Robert C, Long GV, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Rutkowski P, Hassel JC, McNeil CM, Kalinka EA, Lebbe C, Charles J, Hernberg MM, Savage KJ, Chiarion-Sileni V, Mihalcioiu C, Mauch C, Arance A, Cognetti F, Ny L, Schmidt H, Schadendorf D, Gogas H, Zoco J, Re S, Ascierto PA, Atkinson V. Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma. J Clin Oncol. 2020 Nov 20;38(33):3937-3946. doi: 10.1200/JCO.20.00995. Epub 2020 Sep 30.
• Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbe C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Ny L, Arance A, Svane IM, Schadendorf D, Gogas H, Saci A, Jiang J, Rizzo J, Atkinson V. Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. JAMA Oncol. 2019 Feb 1;5(2):187-194. doi: 10.1001/jamaoncol.2018.4514. Erratum In: JAMA Oncol. 2019 Feb 1;5(2):271.
• Long GV, Tykodi SS, Schneider JG, Garbe C, Gravis G, Rashford M, Agrawal S, Grigoryeva E, Bello A, Roy A, Rollin L, Zhao X. Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer. Ann Oncol. 2018 Nov 1;29(11):2208-2213. doi: 10.1093/annonc/mdy408.
• Long GV, Weber JS, Larkin J, Atkinson V, Grob JJ, Schadendorf D, Dummer R, Robert C, Marquez-Rodas I, McNeil C, Schmidt H, Briscoe K, Baurain JF, Hodi FS, Wolchok JD. Nivolumab for Patients With Advanced Melanoma Treated Beyond Progression: Analysis of 2 Phase 3 Clinical Trials. JAMA Oncol. 2017 Nov 1;3(11):1511-1519. doi: 10.1001/jamaoncol.2017.1588.
• Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbe C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. doi: 10.1056/NEJMoa1412082. Epub 2014 Nov 16.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 2, 2021): 418
• Original Estimated Enrollment (submitted: November 2, 2012): 410
• Actual Study Completion Date: May 14, 2021
• Actual Primary Completion Date: June 24, 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

• Men and women ≥18 years of age
• Eastern Cooperative Oncology Group Performance Status of 0 or 1
• Untreated and histologically confirmed unresectable Stage III or Stage IV melanoma, as per the staging system of the American Joint Committee on Cancer
• Measurable disease as per Response Evaluation Criteria in Solid Tumors 1.1
• Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses
• Known BRAF wild-type, as per regionally acceptable V600 mutational status testing. BRAF mutant patients and those with indeterminate or unknown BRAF status are not permitted to randomize

Exclusion Criteria:

• Active brain metastases or leptomeningeal metastases
• Ocular melanoma
• Any active, known, or suspected autoimmune disease

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, Canada, Chile, Denmark, Finland, France, Germany, Greece, Israel, Italy, Mexico, Norway, Poland, Spain, Sweden
• Removed Location Countries: United States

Administrative Information

• NCT Number: NCT01721772
• Other Study ID Numbers: CA209-066; 2012-003718-16 ( 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: Not Provided

Investigators

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

• PRS Account: Bristol-Myers Squibb
• Verification Date: June 2022