1370P - Phase Ib/II study (SENSITIZE) assessing safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical outcome of domatinostat in combination with pembrolizumab in patients with advanced melanoma refractory/non-responding to prior checkpoint inhibitor therapy

Abstract

BackgroundMany advanced melanoma patients are refractory and do not respond to checkpoint inhibition (CI) alone. Epigenetic modulation of tumors to enhance their immunogenicity, alter the tumor microenvironment and thus increase the chance of response to immunotherapy is one clinical approach. In an open label Phase Ib/II multi-center study (‘SENSITIZE’) we investigated the combination of the HDAC inhibitor domatinostat and pembrolizumab in patients with advanced melanoma. MethodsAdvanced stage melanoma patients who were refractory or non-responding to prior checkpoint inhibitor therapy were treated with domatinostat (orally) at increasing dose levels in 3 different dose cohorts in combination with pembrolizumab (2mg/kg) q3w intravenously in a modified “rolling six” study design to evaluate the safety and tolerability of the combination treatment. Tumor assessment was initially performed after 12 weeks. Tumor biopsies were taken for immunohistochemical and gene expression analysis, peripheral blood for PK/PD analysis. ResultsAt time of data cut-off on May 8th, 2019 (study ongoing), a total of 23 patients were enrolled into the study. The safety profile indicates that domatinostat-specific adverse events add to the known safety profile of pembrolizumab, but no exacerbation of immune-related adverse events in rate and severity has been observed so far. Domatinostat alone and in combination was considered safe. First signs of efficacy have been observed, including patients one with a partial response and two with stable disease per irRECIST 1.1. Tumor biopsies at baseline showed a domatinostat-induced alteration of the tumor microenvironment including infiltration of CD8+ T cells, the presence of PD-1/ PD-L1 positive cells, and changes on gene expression levels. Furthermore, a dose-dependent PK profile has been observed. ConclusionsDomatinostat given in combination with pembrolizumab is safe and tolerable and might increase anti-tumor activity in these CI-unresponsive melanoma patients by alteration of the immune tumor microenvironment. Clinical trial identificationNCT03278665. Legal entity responsible for the study4SC AG. Funding4SC AG. DisclosureP.A. Ascierto: Advisory / Consultancy, Travel / Accommodation / Expenses: 4SC. F. Hermann: Full / Part-time employment: 4SC AG. R. Bartz: Full / Part-time employment: 4SC AG. D. Schadendorf: Advisory / Consultancy, Travel / Accommodation / Expenses: 4SC. All other authors have declared no conflicts of interest.