Abstract Background: Brain metastases frequently occur in patients with late-stage cancers. Treatment with high-dose glucocorticoids (GCs) is usually started to prevent or reduce tumor-related edema and its deadly complications. However, treatment with high-dose GCs is associated with serious side effects, including diabetes and immunosuppression, which could promote tumor growth or reduce the effectiveness of antitumor therapies. Based on its potential antitumor properties and on its ability to prevent GC-induced diabetes, the antidiabetic compound Metformin could reduce short-term mortality in patients with brain metastases taking high-dose GCs. Methods: The OPTIMAL study is a monocentric, open label, randomized Phase II trial in patients with brain metastases from melanoma, lung or breast cancer, who require treatment with high-dose dexamethasone, as defined as a minimum of 8 mg daily based on the clinician judgment, for at least three consecutive weeks. At enrollment, patients are randomized in a 1:1 ratio to receive high-dose dexamethasone +/- metformin 2550 mg/day for 30 days. At randomization, patients are stratified according to: tumor origin, dose of dexamethasone (8-12 vs. > 12 mg/day) and baseline fasting glycemia (< 100 vs. 100-125 mg/dl). Patients may receive concomitant radiotherapy based on the judgment of the physician. The primary study endpoint is the rate of precocious (14 days) dexamethasone-induced diabetes, as defined as fasting plasma glucose levels ≥ 126 mg/dl. Discussion: The OPTIMAL study aims to evaluate the efficacy of upfront use of metformin in preventing the onset of GCs-induced diabetes and other metabolic perturbations in patients with brain metastases from melanoma, lung or breast cancer. Other clinical objectives consist in investigating the impact of metformin on precocious mortality, deterioration of ECOG PS and local (brain) disease control rate at one month after dexamethasone initiation. The effect of dexamethasone +/- metformin on other metabolites or growth factors, including amino acids, fatty acids, ketone bodies, IGF-1, as well as on the number, activation status and metabolism of peripheral blood immune cell populations will be evaluated as well. Trial registration: The OPTIMAL trial is registered at ClinicalTrials.gov (NCT04001725, June 28, 2019) and EudraCT (2019-000105-73, January 8, 2019). Citation Format: Claudio Vernieri, Federico Nichetti, Francesca Ligorio, Emma Zattarin, Teresa Beninato, Riccardo Lobefaro, Giulia Bianchi, Giuseppe Capri, Marina Garassino, Giuseppe Lo Russo, Michele Del Vecchio, Paola Corsetto, Licia Rivoltini, Chiara Castelli, Filippo de Braud. Efficacy of metfOrmin in PrevenTIng glucocorticoid-induced diabetes in Melanoma, breAst or Lung Cancer patients with brain metastases: The phase II OPTIMAL study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT198.