Time-of-Day Specified Ipilimumab and Nivolumab for the Treatment of Stage IV Unresectable Melanoma, The TIME Trial

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion Criteria

Inclusion Criteria:

- 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) - Eastern Cooperative Oncology Group (ECOG) 0-1.

- Age ≥ 18.

- Adequate organ function to receive ipilimumab/nivolumab.

Exclusion Criteria:

- Immunosuppression (> 10mg prednisone daily) - Active autoimmune disease that would preclude the administration of immunotherapy.

- Active leptomeningeal disease

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT07155317
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 2
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Emory University
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Michael Lowe, MD, MA
Principal Investigator Affiliation	Emory University Hospital/Winship Cancer Institute
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other, NIH
Overall Status	Not yet recruiting
Countries	United States
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	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

Additional Details

PRIMARY OBJECTIVE:

I. To compare the progression-free survival (PFS) following administration of immunotherapy at different time-of-day intervals for previously untreated unresectable or metastatic melanoma.

SECONDARY OBJECTIVES:

I. To compare adverse events (AEs).

II. Rate of receiving all immunotherapy doses as scheduled.

III. Objective response rate.

IV. Melanoma specific survival (MSS) and overall survival (OS).

V. Patient-reported quality of life (QOL).

TERTIARY/EXPLORATORY OBJECTIVE:

I. To explore immune biomarkers associated with clinical efficacy (PFS, OS).

OUTLINE: Patients are randomized to 1 of 3 arms. ARM I: Patients receive nivolumab intravenously (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, computed tomography (CT) or magnetic resonance imaging (MRI) and MRI or CT of brain throughout the study. Additionally, patients may optionally undergo tumor tissue biopsy throughout the study. ARM II: 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: 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. After completion of study treatment, patients are followed up every 3 months for 12 months, then for up to year 5.

Arms & Interventions

Arms

Experimental: Arm I (nivolumab, ipilimumab)

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.

Experimental: Arm II (nivolumab, ipilimumab)

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.

Active Comparator: Arm III (nivolumab, ipilimumab)

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.

Interventions

Procedure: - Biopsy Procedure

Undergo tumor tissue biopsy

Procedure: - Biospecimen Collection

Undergo check swab and blood sample collection

Procedure: - Computed Tomography

Undergo CT

Biological: - Ipilimumab

Given IV

Procedure: - Magnetic Resonance Imaging

Undergo MRI

Other: - Medical Device Usage and Evaluation

Wear an actigraphy device

Biological: - Nivolumab

Given IV

Other: - Questionnaire Administration

Ancillary studies

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Atlanta 4180439, Georgia 4197000

Status

Address

Emory University Hospital/Winship Cancer Institute

Atlanta 4180439, Georgia 4197000, 30322

Site Contact

Tiffaney Roundtree

[email protected]

404-778-0680

Emory Saint Joseph's Hospital, Atlanta 4180439, Georgia 4197000

Status

Address

Emory Saint Joseph's Hospital

Atlanta 4180439, Georgia 4197000, 30342

Site Contact

Tiffaney Roundtree

[email protected]

404-778-0680

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