Time-of-Day Specified Immunotherapy for Advanced Melanoma, The TIME Trial

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.

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