A Study of NKTR-214 Combined With Nivolumab vs Nivolumab Alone in Participants With Previously Untreated Inoperable or Metastatic Melanoma

• ClinicalTrials.gov Identifier: NCT03635983
• Recruitment Status: Active, not recruiting
• First Posted: August 17, 2018
• Results First Posted: December 19, 2022
• Last Update Posted: May 10, 2023
• Sponsor: Bristol-Myers Squibb
• Collaborator: Nektar Therapeutics
• Information provided by (Responsible Party): Bristol-Myers Squibb

Tracking Information

• First Submitted Date: August 16, 2018
• First Posted Date: August 17, 2018
• Results First Submitted Date: November 18, 2022
• Results First Posted Date: December 19, 2022
• Last Update Posted Date: May 10, 2023
• Actual Study Start Date: September 21, 2018
• Actual Primary Completion Date: November 19, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 18, 2022)

• Objective Response Rate (ORR) Per Blinded Independent Central Review (BICR) [ Time Frame: From date of randomization to disease progression (Up to 37 months) ]
  ORR is defined as the percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR) using RECIST v 1.1 per blinded independent central review (BICR) assessment. CR=Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR=At least a 30% decrease in the sum of diameters of target lesions.
• Progression-free Survival (PFS) Per Blinded Independent Central Review (BICR) [ Time Frame: From date of randomization to disease progression, or death, whichever comes first (Up to 37 months) ]
  PFS is defined as the time between the date of randomization and the first date of documented tumor progression using RECIST v 1.1 per blinded independent central review (BICR), or death due to any cause, whichever comes first. Progressive disease (PD)=At least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an absolute increase of at least 5 mm.
• Overall Survival (OS) [ Time Frame: From date of randomization to date of death (Up to 37 months) ]
  OS is defined as the time between the date of randomization and the date of death due to any cause. Participants who do not have a date of death will be censored on the last date for which a participant was known to be alive.

Original Primary Outcome Measures (submitted: August 16, 2018)

• Overall response rate (ORR) by Blinded Independent Central Review (BICR) [ Time Frame: Approximately 16 months ]
• Progression-free survival (PFS) by BICR [ Time Frame: Approximately 22 months ]
• Overall survival (OS) [ Time Frame: Up to 59 months ]

Current Secondary Outcome Measures (submitted: November 18, 2022)

• Clinical Benefit Rate (CBR) Per Blinded Independent Central Review (BICR) [ Time Frame: From date of randomization to disease progression (Up to 37 months) ]
  CBR, or equivalently the disease control rate (DCR) is defined as the percentage of participants with a best overall response of complete response (CR), partial response (PR), or stable disease (SD) as assessed by blinded independent central review (BICR) using RECIST v 1.1. CR=Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR=At least a 30% decrease in the sum of diameters of target lesions.SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease.
• Duration of Response (DoR) Per Blinded Independent Central Review (BICR) [ Time Frame: From date of randomization to disease progression, or death, whichever is earlier (Up to 37 months) ]
  DOR is defined for participants who have a confirmed complete response (CR) or partial results (PR) as the date from first documented CR or PR using RECIST v 1.1 to the date of the documentation of disease progression per blinded independent central review (BICR) assessment or death due to any cause, whichever is earlier. CR=Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR=At least a 30% decrease in the sum of diameters of target lesions.
• Time to Objective Response (TTR) Per Blinded Independent Central Review (BICR) [ Time Frame: From date of randomization to disease progression (Up to 37 months) ]
  Time to response (TTR) is defined for participants who had a confirmed complete response (CR) or partial response (PR) as the time from the date of randomization to date of first documented CR or PR per blinded independent central review (BICR) assessment using RECIST v 1.1. CR=Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR=At least a 30% decrease in the sum of diameters of target lesions.
• Objective Response Rate (ORR) Per Investigator [ Time Frame: From date of randomization to disease progression (Up to 37 months) ]
  ORR is defined as the percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR) using RECIST v 1.1 per investigator assessment. CR=Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR=At least a 30% decrease in the sum of diameters of target lesions.
• Progression-free Survival (PFS) Per Investigator [ Time Frame: From date of randomization to disease progression, or death, whichever comes first (Up to 37 months) ]
  PFS is defined as the time between the date of randomization and the first date of documented tumor progression using RECIST v 1.1 per investigator, or death due to any cause, whichever comes first. Progressive disease (PD)=At least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an absolute increase of at least 5 mm.
• Clinical Benefit Rate (CBR) Per Investigator [ Time Frame: From date of randomization to disease progression (Up to 37 months) ]
  CBR, or equivalently the disease control rate (DCR) is defined as the percentage of participants with a best overall response of complete response (CR), partial response (PR), or stable disease (SD) as assessed by investigator using RECIST v 1.1. CR=Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR=At least a 30% decrease in the sum of diameters of target lesions. SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
• Duration of Response (DoR) Per Investigator [ Time Frame: From date of randomization to disease progression, or death, whichever is earlier (Up to 37 months) ]
  DOR is defined for participants who have a confirmed complete response (CR) or partial results (PR) as the date from first documented CR or PR using RECIST v 1.1 to the date of the documentation of disease progression per investigator assessment or death due to any cause, whichever is earlier. CR=Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR=At least a 30% decrease in the sum of diameters of target lesions.
• Time to Objective Response (TTR) Per Investigator [ Time Frame: From date of randomization to disease progression (Up to 37 months) ]
  Time to response (TTR) is defined for participants who had a confirmed complete response (CR) or partial response (PR) as the time from the date of randomization to date of first documented CR or PR per investigator assessment using RECIST v 1.1. CR=Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR=At least a 30% decrease in the sum of diameters of target lesions.
• Objective Response Rate (ORR) Per Blinded Independent Central Review (BICR) by Baseline PD-L1 Status [ Time Frame: From date of randomization to disease progression (Up to 37 months) ]
  ORR by baseline PD-L1 tumor cells expression (PD-L1 negative: <1%) vs. (PD-L1 positive: >=1%). ORR is defined as the percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR) using RECIST v 1.1 per blinded independent central review (BICR) assessment. CR=Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR=At least a 30% decrease in the sum of diameters of target lesions.
• Progression-free Survival (PFS) Per Blinded Independent Central Review (BICR) by Baseline PD-L1 Status [ Time Frame: From date of randomization to disease progression, or death, whichever comes first (Up to 37 months) ]
  PFS by baseline PD-L1 tumor cells expression (PD-L1 negative: <1%) vs. (PD-L1 positive: >=1%). PFS is defined as the time between the date of randomization and the first date of documented tumor progression using RECIST v 1.1 per blinded independent central review (BICR), or death due to any cause, whichever comes first. Progressive disease (PD)=At least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an absolute increase of at least 5 mm.
• Overall Survival (OS) by Baseline PD-L1 Status [ Time Frame: From date of randomization to date of death (Up to 37 months) ]
  OS by baseline PD-L1 tumor cells expression (PD-L1 negative: <1%) vs. (PD-L1 positive: >=1%). OS is defined as the time between the date of randomization and the date of death due to any cause. Participants who do not have a date of death will be censored on the last date for which a participant was known to be alive.
• Number of Participants With Adverse Events (AEs) [ Time Frame: From first dose to 30 days post last dose (Average of 8 months and a maximum up to 35 months) ]
  Number of participants with any grade adverse events (AEs) including treatment-related AEs, AEs leading to discontinuation of any drug, serious adverse events (SAEs), treatment-related SAEs, and deaths from first dose to 30 days post last dose. An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment.
• Number of Participants With On-Treatment Laboratory Parameters That Worsened Relative to Baseline [ Time Frame: From first dose to 100 days post last dose (Average of 10 months and a maximum up to 37 months) ]
  Number of participants with on-treatment laboratory parameters that worsened relative to baseline. Parameters include hematology, chemistry, liver function, and renal function using worst grade (grade 1-4 and grade 3-4) per national cancer institute (NCI) common terminology criteria for adverse events (CTCAE) v5 criteria. Grade 1=Mild event Grade 2=Moderate event Grade 3=Severe event Grade 4=Life threatening event

Original Secondary Outcome Measures (submitted: August 16, 2018)

• Clinical benefit rate (CBR) [ Time Frame: Approximately 16 months ]
• Duration of response (DoR) [ Time Frame: Approximately 16 months ]
• Duration of overall complete response (DoCR) [ Time Frame: Approximately 16 months ]
• Time to response (TTR) [ Time Frame: Approximately 16 months ]
• ORR by investigator and in biomarker population [ Time Frame: Approximately 16 months ]
• PFS by investigator and in biomarker population [ Time Frame: Approximately 22 months ]
• OS in biomarker population [ Time Frame: Up to 59 months ]
• Incidence of participants with non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) leading to discontinuation [ Time Frame: Up to 5 years ]
• Incidence of treatment-related AEs [ Time Frame: Up to 5 years ]
• Incidence of treatment-related SAEs [ Time Frame: Up to 5 years ]
• Incidence of laboratory abnormalities [ Time Frame: Up to 5 years ]

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

Descriptive Information

• Brief Title: A Study of NKTR-214 Combined With Nivolumab vs Nivolumab Alone in Participants With Previously Untreated Inoperable or Metastatic Melanoma
• Official Title: A Phase 3, Randomized, Open-label Study of NKTR-214 Combined With Nivolumab Versus Nivolumab in Participants With Previously Untreated Unresectable or Metastatic Melanoma
• Brief Summary: The purpose of the study is to test the effectiveness (how well the drug works), safety, and tolerability of the investigational drug called NKTR-214, when combined with nivolumab versus nivolumab given alone in participants with previously untreated melanoma skin cancer that is either unable to be surgically removed or has spread
• 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: Melanoma

Intervention

• Biological: NKTR-214
  Specified dose on specified days
  Other Names:

  • Bempegaldesleukin
  • BMS-986321
• Biological: Nivolumab
  Specified dose on specified days
  Other Names:

  • Opdivo
  • BMS-936558

Study Arms

• Experimental: Combination
  NKTR-214 + Nivolumab
  Interventions:

  • Biological: NKTR-214
  • Biological: Nivolumab
• Experimental: Monotherapy
  Nivolumab
  Intervention: Biological: Nivolumab

• Publications *: Khushalani NI, Diab A, Ascierto PA, Larkin J, Sandhu S, Sznol M, Koon HB, Jarkowski A, Zhou M, Statkevich P, Geese WJ, Long GV. Bempegaldesleukin plus nivolumab in untreated, unresectable or metastatic melanoma: Phase III PIVOT IO 001 study design. Future Oncol. 2020 Oct;16(28):2165-2175. doi: 10.2217/fon-2020-0351. Epub 2020 Jul 29.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: June 17, 2022): 783
• Original Estimated Enrollment (submitted: August 16, 2018): 764
• Estimated Study Completion Date: February 26, 2024
• Actual Primary Completion Date: November 19, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 (adults 18 years or older)/Lansky Performance Score ≥ 80% (minors ages 12-17 only)
• Histologically confirmed stage III (unresectable) or stage IV melanoma
• Treatment-naive participants (ie, no prior systemic anticancer therapy for unresectable or metastatic melanoma) with the exception of prior adjuvant and/or neoadjuvant treatment for melanoma with approved agents

Exclusion Criteria:

• Active brain metastases or leptomeningeal metastases
• Uveal melanoma
• Participants with an active, known or suspected autoimmune disease

Other protocol defined inclusion/exclusion criteria apply

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, 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, Belgium, Brazil, Canada, Chile, Czechia, Finland, France, Germany, Greece, Ireland, Israel, Italy, Mexico, Netherlands, New Zealand, Poland, Portugal, Romania, Russian Federation, Spain, Sweden, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT03635983
• Other Study ID Numbers: CA045-001; 2018-001423-40 ( EudraCT Number ); 17-214-08 ( Other Identifier: Nektar Therapeutics )
• 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: Nektar Therapeutics

Investigators

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

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