Brief Summary

This phase II trial tests the safety and effectiveness of giving ipilimumab and nivolumab in the morning compared to other times of day in treating patients with melanoma that is stage IV or that cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the tumor and may interfere with the ability of tumor cells to grow and spread. While some patients have impressive outcomes with both of these drugs, over 40% of patients do not experience any clinical benefit. Studies have shown that the time of day that vaccines and other therapies are given have had an impact on response and survival. It is not known, however, whether time of day has an impact on response to immune checkpoint inhibitors, such as ipilimumab and nivolumab. Giving ipilimumab and nivolumab earlier in the day compared to later in the day may improve response to treatment and survival in patients with stage IV or unresectable melanoma.

Trial Health

On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment

participants targeted

Target at P50-P75 for phase_2

Timeline

20mo left

Started Oct 2025

Geographic Reach

1 country

2 active sites

Status

recruiting

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

2.2 years study duration

Study Progress24%

Oct 2025Dec 2027

First Submitted

Initial submission to the registry

August 21, 2025

Completed

14 days until next milestone

First Posted

Study publicly available on registry

September 4, 2025

Completed

2 months until next milestone

Study Start

First participant enrolled

October 29, 2025

Completed

1.2 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 31, 2026

Expected

1 year until next milestone

Study Completion

Last participant's last visit for all outcomes

December 31, 2027

Last Updated

November 12, 2025

Status Verified

November 1, 2025

Enrollment Period

1.2 years

First QC Date

August 21, 2025

Last Update Submit

November 10, 2025

Conditions

Advanced Acral Melanoma Advanced Cutaneous Melanoma Advanced Mucosal Melanoma Clinical Stage IV Cutaneous Melanoma AJCC v8 Metastatic Acral Melanoma Metastatic Cutaneous Melanoma Metastatic Mucosal Melanoma Unresectable Acral Melanoma Unresectable Cutaneous Melanoma Unresectable Mucosal Melanoma

Outcome Measures

Primary Outcomes (1)

Progression-Free Survival (PFS) A versus (vs.) C and B vs. C
Will be determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Will be compared between arms with a log rank test. The hazard ratio and the corresponding 95% confidence interval (CI) for the A vs. C and B vs. C comparisons will be estimated in a Cox proportional hazards model using the randomized arm as a single covariate. The PFS curves for each randomized arm will be estimated using the Kaplan-Meier (KM) method. In addition, PFS rates at specific time points will be estimated using KM estimates on the PFS curve for each randomized arm. Associated 2-sided 95% CIs will be calculated using the Greenwood formula (using log-log transformation).
From randomization to progression or death, assessed up to 5 years

Secondary Outcomes (6)

Incidence of Treatment-Related Adverse Events (AE)
Up to 100 days after last dose of study treatment
Objective Response Rate (ORR)
Up to 3 months
Overall Survival (OS)
From randomization to death from any cause, assessed up to 5 years
PFS A vs. B
From randomization to progression or death, assessed up to 5 years
Disease Specific Survival
Up to 5 years
+1 more secondary outcomes

Study Arms (3)

Arm I (nivolumab, ipilimumab)

EXPERIMENTAL

Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes at 0800-1100 on day 1 of each cycle. Cycles repeat every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance nivolumab for up to a total of 2 years. Patients wear an actigraphy device for 5-7 days at enrollment prior to first infusion and for up to 4 weeks then over 3 weeks starting with visit 4. Patients also undergo check swab and blood sample collection, CT or MRI and MRI or CT of brain throughout the study. Additionally, patients may optionally undergo tumor tissue biopsy throughout the study.

Procedure: Biopsy ProcedureProcedure: Biospecimen CollectionProcedure: Computed TomographyBiological: IpilimumabProcedure: Magnetic Resonance ImagingOther: Medical Device Usage and EvaluationBiological: NivolumabOther: Questionnaire Administration

Arm II (nivolumab, ipilimumab)

EXPERIMENTAL

Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes at 1100-1400 on day 1 of each cycle. Cycles repeat every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance nivolumab for up to a total of 2 years. Patients wear an actigraphy device for 5-7 days at enrollment prior to first infusion and for up to 4 weeks then over 3 weeks starting with visit 4. Patients also undergo check swab and blood sample collection, CT or MRI and MRI or CT of brain throughout the study. Additionally, patients may optionally undergo tumor tissue biopsy throughout the study.

Arm III (nivolumab, ipilimumab)

ACTIVE COMPARATOR

Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes at 1400-1700 on day 1 of each cycle. Cycles repeat every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance nivolumab for up to a total of 2 years. Patients wear an actigraphy device for 5-7 days at enrollment prior to first infusion and for up to 4 weeks then over 3 weeks starting with visit 4. Patients also undergo check swab and blood sample collection, CT or MRI and MRI or CT of brain throughout the study. Additionally, patients may optionally undergo tumor tissue biopsy throughout the study.