MELCHRONO: A Prospective Randomized Study Investigating Chrono-immunotherapy for Advanced Melanoma.

Melanoma remains a common cancer with rising incidence, and despite significant improvements with immune checkpoint inhibitors (ICIs), clinical outcomes remain heterogeneous. Retrospective analyses across multiple tumor types, including melanoma, suggest that earlier daytime administration of ICIs may enhance therapeutic effectiveness, potentially due to circadian modulation of immune function. A pronounced survival benefit has been observed particularly among female patients receiving earlier infusions. This trial prospectively evaluates whether aligning ICI administration with circadian immune activity can improve outcomes in melanoma and support the development of sex-specific optimization of immunotherapy.

Inclusion Criteria: * Written informed consent according to Swiss law and ICH GCP E6 regulations before registration and prior to any trial specific procedures. * Histologically confirmed unresectable cutaneous stage III or stage IV melanoma. Note: Participants with central nervous system (CNS) metastases are eligible. * Participants with a previously treated other malignancy are eligible, if the risk of the prior malignancy interfering with either safety or efficacy endpoints is very low. * Measurable or evaluable disease. * Age ≥ 18 years. * Patients deemed suitable for ICI therapy based on the local investigator's clinical assessment. * ECOG performance status 0-2. * Women of childbearing potential must use effective contraception , not be pregnant or lactating and agree not to become pregnant during trial treatment and until 5 months after the last dose of trial treatment. A negative pregnancy test before inclusion into the trial is required for all women of childbearing potential. * Men agree not to donate sperm or to father a child during trial treatment and until 5 months after the last dose of trial treatment. Exclusion Criteria: * Prior treatment with any systemic anti-cancer therapy; with the exception of prior adjuvant anti-PD-1 or BRAF/MEK inhibitor therapy if the time from last dose to recurrence is more than 6 months. * Recent treatment (within 28 days prior to first dose) with any experimental drug. * Known history of allogeneic organ transplant. * Uveal or mucosal melanoma. * Receipt of live attenuated vaccine within 28 days prior to first dose. * Any concomitant drugs contraindicated for use with the trial drugs according to the approved product information. * Known hypersensitivity to trial drug(s) or to any component of the trial drug(s). * Any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned staging, treatment and follow-up, affect participant compliance or place the participant at high risk from treatment-related complications.