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.
Pathologically confirmed American Joint Committee on Cancer (AJCC) 8th edition stage IV unresectable cutaneous, acral, or mucosal melanoma
No uveal melanoma
Patients with asymptomatic, non-hemorrhagic brain metastases < 2 cm are eligible
No prior immunotherapy within 1 year, (serine/threonine-protein kinase B-raf [BRAF]/mitogen-activated protein kinase [MEK] inhibitors allowed)
Immunosuppression (> 10mg prednisone daily)
Active autoimmune disease that would preclude the administration of immunotherapy
Active leptomeningeal disease
Parallel
Biopsy Procedure
Procedure/SurgeryUndergo tumor tissue biopsy
Biospecimen Collection
Procedure/SurgeryUndergo check swab and blood sample collection
Computed Tomography
Procedure/SurgeryUndergo CT
Ipilimumab
Biological/VaccineGiven IV
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Medical Device Usage and Evaluation
Other interventionWear an actigraphy device
Nivolumab
Biological/VaccineGiven IV
Questionnaire Administration
Other interventionAncillary studies
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).
Incidence of Treatment-Related Adverse Events (AE)
Will be determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5. Frequencies and percentages will be used to summarize safety events. All treatment-associated AE event rates, as well as treatment-associated grade 3 or higher AE event rates will be reported. Event rates will be compared between arms using a Chi-square test. Differences in event rates will be reported, and 95% CIs will be estimated.
Objective Response Rate (ORR)
Will be defined as complete response and/or partial response assessed using RECIST 1.1 criteria. Will be estimated as a proportion, with an exact 95% CI estimated using the Clopper-Pearson method. ORR will be compared between arms using a Chi-square test.
Overall Survival (OS)
Will be compared between arms with a log rank test. The hazard ratio and the corresponding 95% CIs 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 OS curves for each randomized arm will be estimated using the KM method. In addition, OS rates at specific time points will be estimated using KM estimates on the OS curve for each randomized arm. Associated 2-sided 95% CIs will be calculated using the Greenwood formula (using log-log transformation).
PFS A vs. B
Will be determined using RECIST 1.1. PFS will be compared between arms with a log rank test. The hazard ratio and the corresponding 95% CI for the A vs. B comparison 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 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).
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Emory University
Lead sponsor
National Cancer Institute (NCI)
Collaborator
