Timing of Immunotherapy in Melanoma

The TIME-NL trial is a multicenter, randomized, open-label clinical trial in the Netherlands to assess the effect of the timing of the first administration of standard-of-care intravenous combination immunotherapy (early morning versus afternoon) in patients with metastatic melanoma. Patients will be randomized 1:1 to start standard-of-care ICI administration either before 10am (early morning arm; arm A) or after 1pm (afternoon arm; arm B). Patients will be stratified according to performance status and study center. The randomized clinical trial will be part of a hybrid design in which data from the randomized clinical trial will be combined with observational data.

Inclusion Criteria: * Histologically or cytologically confirmed cutaneous melanoma, classified as irresectable (stage III) or metastatic (stage IV) disease. * At least 18 years of age. * World Health Organization (WHO) Performance Status 0-1. * Measurable disease according to RECIST 1.1. * Starting treatment with standard-of-care combination immunotherapy (ipilimumab+nivolumab) as first line treatment. * Signed informed consent form Exclusion Criteria: * Uveal or mucosal melanoma (unknown primary melanoma is allowed). * Use of systemic immunosuppressive medications. Inhaled or topical steroids are permitted. * Use of adrenal replacement medications, e.g. hydrocortisone. * Use of melatonin agonists. * Prior systemic therapy for irresectable/metastatic melanoma (prior T-VEC is allowed) * Prior systemic therapy for resectable melanoma in the last 6 months (neo-adjuvant and adjuvant treatment is allowed if at least 6 months ago). * Use of investigational drugs.