Preclinical and clinical studies of a class I/IV HDAC inhibitor, mocetinostat, in melanoma.

Abstract

10052 Background: Mocetinostat is a class I/IV HDAC inhibitor with HDAC1/2/3/11 activity. Preclinical murine data suggest that HDAC inhibition has immune activity and may augment the clinical benefit of checkpoint inhibition. Several trials are assessing the effects of adding HDAC inhibition to PD-1 blockade. Methods: Patients with therapy-naive metastatic melanoma were treated in a pilot phase Ib trial with nivolumab at 3 mg/kg/ipilimumab at 1 mg/kg every three weeks four times and a starting dose of mocetinostat at 70 mg orally three times a week in a 12-week induction cycle followed by 12-week maintenance cycles of nivolumab 240 mg every 2 weeks and mocetinostat at the same dose and schedule as induction. Endpoints were toxicity, definition of a recommended phase 2 dose and preliminary assessment of response as well as correlative marker determination. Peripheral blood mononuclear blood cells from patients were tested in vitro at varying concentrations of mocetinostat, and its impact on T, regulatory T and myeloid-derived suppressor cell phenotypes were assessed by flow cytometry, as well as cytokine production by Luminex. Results: In the mocetinostat, nivolumab and ipilimumab phase I trial, 10 patients were treated, including 5 males and 5 females with a median age of 59. There were 2 complete and 5 partial responses confirmed; 6 of 7 are maintained at a median of 16 months of follow up. Three patients had progressive disease. Seven patients had grade 3-4 immune related adverse events; in 3 they were multiple. No patients died. In vitro, mocetinostat at doses from 125 to 500 nM increased relative percentage of CD4/CD8 central memory T cells, and decreased IL-6 levels while increasing interferon-gamma production (p = 0.005). Percentages of regulatory T and monocytic myeloid-derived suppressor cells were decreased by mocetinostat (p = 0.005), which also down-modulated regulatory T cell function by reducing FOXP3, HELIOS and GARP (p = 0.001). Conclusions: In vitro, mocetinostat promoted accumulation of central memory CD8 and CD4 T cells from melanoma patients, and decreased percentages and suppressive activity of T regulatory cells and myeloid-derived suppressor cells. In a pilot clinical trial, mocetinostat combined with nivolumab and ipilimumab in treatment-naïve metastatic melanoma patients exhibited a response rate of 70% with long duration of response but all ten patients treated had at least one grade 3 or 4 immune-related toxicity. De-escalation of the mocetinostat dose to 50 mg three times a week was felt to be indicated due to the toxicity of the triple regimen. Clinical trial information: NCT03565406.