Effectiveness Study of Nivolumab Compared to Placebo in Prevention of Recurrent Melanoma After Complete Resection of Stage IIB/C Melanoma

A Phase 3, Randomized, Double-Blind Study of Adjuvant Immunotherapy With Nivolumab Versus Placebo After Complete Resection of Stage IIB/C Melanoma

Status

Active, not recruiting

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04099251

Acronym

CheckMate76K

Enrollment

790

Registered

2019-09-23

Start date

2019-10-28

Completion date

2026-11-30

Last updated

2026-08-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Melanoma

Brief summary

The purpose of this study is to determine the effectiveness of nivolumab adjuvant immunotherapy compared to placebo in adults and pediatric participants after complete resection of Stage IIB/C melanoma with no evidence of disease (NED) who are at high risk for recurrence.

Interventions

BIOLOGICALNivolumab

Specified dose on specified days

OTHERPlacebo

Specified dose on specified days

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

12 Years to No maximum

Healthy volunteers

Inclusion criteria

* Had a negative sentinel lymph node biopsy. * Participant has not been previously treated for melanoma. * ECOG 0 or 1. * Participants must have been diagnosed with histologically confirmed, Resected, Stage IIB/C cutaneous melanoma.

Exclusion criteria

* History of ocular or mucosal melanoma. * Pregnant or nursing women. * Participants with active known or suspected autoimmune disease. * Known history of allergy or hypersensitivity to study drug components. * Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 antibody, or agents that target IL-2 pathways, T-cell stimulators, or checkpoint pathways. Other protocol defined inclusion/

Design outcomes

Primary

Measure	Time frame	Description
Recurrence Free Survival (RFS)	From randomization up to the date of first recurrence, new primary melanoma, or death (whatever the cause), whichever occurs first (up to 32 months)	Recurrence Free Survival (RFS) is defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (whatever the cause), whichever occurs first. For participants who remain alive and whose disease has not recurred or did not die, RFS will be censored on the date of last evaluable disease assessment. For those participants who remained alive and had no recorded post-randomization tumor assessment, RFS will be censored on the day of randomization.

Secondary

Measure	Time frame	Description
Distant Metastasis-Free Survival (DMFS)	From randomization up to the date of first distant metastasis or date of death (whatever the cause), whichever occurs first (up to approximately 32 months)	Investigator-assessed distant metastasis-free survival (DMFS) is defined as the time between the date of randomization and the date of first distant metastasis or date of death (whatever the cause), whichever occurs first. Participants with no baseline disease assessment, no on-study disease assessments and no death, and no distant metastasis and no death will be censored. Participants with no baseline disease assessment and no on-study disease assessments and death are censored on the date of randomization. Participants with no recurrence and no death will be censored on the date of their last evaluable disease assessment.
Duration of Treatment on Next Line Therapy Per Investigator Assessment	From first dose date of next-line therapy to last dose date of next-line therapy (up to approximately 32 months)	Duration of treatment is an investigator-assessed outcome of next-line therapy (NLT) defined as the time from first dose date of NLT to last dose date of NLT. Participants who did not stop the NLT were censored.
Progression-Free Survival Through Next-Line Therapy	From randomization to recurrence/objective disease progression after the start of the next-line therapy, or to the start of a second next-line systemic therapy, or to death from any cause, whichever occurs first (up to approximately 32 months)	Progression-free survival through next-line therapy (PFS2) is defined as the time from randomization to recurrence/objective disease progression after the start of the next-line of systemic anti-cancer therapy, or to the start of a second next-line systemic therapy, or to death from any cause, whichever occurs first. Participants who did not receive subsequent systemic anti-cancer therapy who died will be considered as having the event on the date of death. Participants who received subsequent systemic anti-cancer therapy who had a disease progression after the start of therapy will be considered as having the event on the date of disease progression. Participants who died or started second next-line therapy, the date of death or start date of second next-line therapy will be the event date, whichever is earlier. Participants who did not experience disease progression, death, or second next-line therapy will be censored on the last known alive date.
Number of Participants Experiencing Adverse Events (AEs)	From first dose up to 30 days post last dose of the blinded phase (up to 13 months)	An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Adverse events are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events are fatal.
Number of Participants Experiencing Adverse Events Leading to Discontinuation	From first dose up to 30 days post last dose of the blinded phase (up to 13 months)	An Adverse Event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure.
Number of Participants Experiencing Select Adverse Events	From first dose up to 30 days post last dose of the blinded phase (up to 13 months)	The number of participants experiencing all-cause select adverse events (AEs). An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure.
Number of Participants Experiencing Serious Adverse Events (SAEs)	From first dose up to 30 days post last dose of the blinded phase (up to 13 months)	A Serious Adverse Events (SAE) is defined as any untoward or unfavorable medical occurrence in a participants that results in death, is life threatening, or places the participant at immediate risk of death from the event as it occurred, requires or prolongs hospitalization, causes persistent or significant disability or incapacity, results in congenital anomalies or birth defects, and is another condition which investigators judge to represent significant hazards.
Number of Participants Experiencing Death	From first dose up to 30 days post last dose of the blinded phase (up to 13 months)	All study participants who died during the blinded phase of the study following treatment.
Number of Participants Experiencing Grade 3 or 4 Laboratory Abnormalities in Selected Hematology Parameters	From first dose up to 30 days post last dose of the blinded phase (up to 13 months)	The number of participants experiencing Grade 3 or 4 laboratory abnormalities in the specific pre-determined hematology tests.
Number of Participants Experiencing Laboratory Abnormalities in Selected Liver Parameters	From first dose up to 30 days post last dose of the blinded phase (up to 13 months)	The number of participants experiencing laboratory abnormalities in the specific pre-determined liver tests.
Overall Survival (OS)	From randomization up to the date of death or the last date the participant was known to be alive	OS is defined as the time between the date of randomization and the date of death. For those without documentation of death, OS will be censored on the last date the participant was known to be alive.

Countries

Australia, Austria, Belgium, Canada, Czechia, Denmark, Finland, France, Germany, Greece, Italy, Netherlands, Norway, Poland, Romania, Spain, Sweden, Switzerland, United Kingdom, United States

Contacts

STUDY_DIRECTORBristol-Myers Squibb

Bristol-Myers Squibb

Participant flow

Pre-assignment details

980 participants were screened, of which 790 participants were randomized (526 nivolumab/264 placebo) into the study and 788 received either the Nivolumab treatment (524 participants) or placebo (264 participants). 30 eligible participants (2 from the Nivolumab treatment arm and 28 from the placebo arm) received open-label Nivolumab treatment during an optional open-label phase.

Participants by arm

Arm	Count
Nivolumab Participants received 480 mg IV Nivolumab in an approximately 30-minute infusion on Day 1 of each 4-week treatment cycle until unacceptable toxicity, withdrawal of consent, completion of 12 months of treatment (from first dose of study treatment), disease recurrence, or the study ends, whichever occurred first. Participants began study treatment (Cycle 1) within 3 calendar days of randomization. Subsequent cycles were initiated within ± 3 days of the target visit date.	526
Placebo Nivolumab matched placebo (0.9% Sodium Chloride for Injection/5% Dextrose for Injection) IV in a 30-minute infusion on Day 1 of each 4-week treatment cycle until unacceptable toxicity, withdrawal of consent, completion of 12 months of treatment (from first dose of study treatment), disease recurrence, or the study ends, whichever occurred first. In the event of disease recurrence, participants on the blinded nivolumab or placebo portion will be offered the option to receive open-label on-protocol nivolumab treatment. Participants received 480 mg IV Nivolumab in a 30-minute infusion on Day 1 of each 4-week treatment cycle until unacceptable toxicity, recurrence/progression, withdrawal of consent, completion of 12 months of treatment from first dose of open-label study treatment, whichever occurred first.	264
Total	790

Baseline characteristics

Characteristic	Placebo	Total	Nivolumab
Age, Continuous	59.3 Years STANDARD_DEVIATION 13.6	59.7 Years STANDARD_DEVIATION 13.8	59.9 Years STANDARD_DEVIATION 13.9
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants	17 Participants	11 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	140 Participants	457 Participants	317 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	118 Participants	316 Participants	198 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) Black or African American	1 Participants	3 Participants	2 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants	9 Participants	8 Participants
Race (NIH/OMB) White	262 Participants	777 Participants	515 Participants
Sex: Female, Male Female	103 Participants	307 Participants	204 Participants
Sex: Female, Male Male	161 Participants	483 Participants	322 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	14 / 526	8 / 264	2 / 32
other Total, other adverse events	464 / 524	194 / 264	20 / 30
serious Total, serious adverse events	95 / 524	37 / 264	5 / 30

Outcome results

Primary

Recurrence Free Survival (RFS)

Recurrence Free Survival (RFS) is defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (whatever the cause), whichever occurs first. For participants who remain alive and whose disease has not recurred or did not die, RFS will be censored on the date of last evaluable disease assessment. For those participants who remained alive and had no recorded post-randomization tumor assessment, RFS will be censored on the day of randomization.

Time frame: From randomization up to the date of first recurrence, new primary melanoma, or death (whatever the cause), whichever occurs first (up to 32 months)

Population: All randomized participants

Arm	Measure	Value (MEDIAN)
Nivolumab	Recurrence Free Survival (RFS)	NA Months
Placebo	Recurrence Free Survival (RFS)	NA Months

p-value: <0.000195% CI: [0.3, 0.59]Regression, Cox

Secondary

Distant Metastasis-Free Survival (DMFS)

Investigator-assessed distant metastasis-free survival (DMFS) is defined as the time between the date of randomization and the date of first distant metastasis or date of death (whatever the cause), whichever occurs first. Participants with no baseline disease assessment, no on-study disease assessments and no death, and no distant metastasis and no death will be censored. Participants with no baseline disease assessment and no on-study disease assessments and death are censored on the date of randomization. Participants with no recurrence and no death will be censored on the date of their last evaluable disease assessment.

Time frame: From randomization up to the date of first distant metastasis or date of death (whatever the cause), whichever occurs first (up to approximately 32 months)

Population: All randomized participants

Arm	Measure	Value (MEDIAN)
Nivolumab	Distant Metastasis-Free Survival (DMFS)	NA Months
Placebo	Distant Metastasis-Free Survival (DMFS)	NA Months

Secondary

Duration of Treatment on Next Line Therapy Per Investigator Assessment

Duration of treatment is an investigator-assessed outcome of next-line therapy (NLT) defined as the time from first dose date of NLT to last dose date of NLT. Participants who did not stop the NLT were censored.

Time frame: From first dose date of next-line therapy to last dose date of next-line therapy (up to approximately 32 months)

Population: All randomized participants

Arm	Measure	Value (MEDIAN)
Nivolumab	Duration of Treatment on Next Line Therapy Per Investigator Assessment	4.17 Months
Placebo	Duration of Treatment on Next Line Therapy Per Investigator Assessment	11.14 Months

Secondary

Number of Participants Experiencing Adverse Events (AEs)

An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Adverse events are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events are fatal.