The TIME trial: Phase II randomized controlled trial of time-of-day–specified nivolumab and ipilimumab for advanced melanoma.

TPS2677 Background: Nivolumab/ipilimumab is standard of care for advanced melanoma patients based on Phase III randomized data from the CheckMate 067 trial. The recent 10-year outcomes results were reported with a melanoma specific survival for Nivolumab/ipilimumab of 52%. These data are very encouraging, but 50% of patients still succumb to their disease by 10-years. Preclinical data suggests that the circadian rhythm may influence the anatomic localization, function and activity of T cells, the target of immunotherapy. More T cells in the tumor or tumor-draining lymph node during initial immunotherapy administration may improve clinical responses and long-term outcomes. To investigate this idea, we performed a retrospective analysis, the MEMOIR study, finding that more evening infusions of immunotherapy were associated with significantly worse progression free and overall survival for metastatic melanoma patients. These findings have now been reproduced in other cancer histologies, in a larger meta-analysis, and in pre-clinical mechanistic studies. Considering these data, we hypothesize that evening infusions of immunotherapy will have worse progression free survival than either morning or midday infusions. Methods: The TIME trial is a three-arm phase II study of time-of-day specified administration of standard dose nivolumab/ipilimumab for metastatic melanoma. For newly diagnosed metastatic melanoma patients enrolled on study, they will be randomized to receive 4 cycles every 3 weeks of nivolumab/ipilimumab between 8:00-11:00 (Arm A), 11:00-14:00 (Arm B), or 14:00-17:00 (Arm C). Following these 4 cycles, they will receive standard of care maintenance nivolumab in a time-of-day agnostic fashion. Eligible patients must have stage IV unresectable cutaneous, acral or mucosal melanoma, no prior immunotherapy within 1 year, ECOG performance status of 0-1, age ≥ 18, no symptomatic or hemorrhagic brain metastases with none greater than 2 cm. The primary objective is to determine whether progression free survival for Arm A or Arm B is superior to Arm C. Secondary objectives include assessments of adverse events, melanoma specific survival and overall survival. We will evaluate the immune profiles of blood and tumor to assess the impact of time of drug administration on the circulating immune responses and the tumor immune microenvironment. 99 patients will be enrolled to detect a HR of 0.50 with at least 80% power and a Type 1 error rate of 0.1 (2-sided) for a comparison of A vs. C, and B vs. C. The study is open at Emory and has enrolled 3 patients; the study is undergoing regulatory review at MGH and Cedars-Sinai. Clinical trial information: NCT07155317 .