Efficacy, safety, tolerability, and PK of the HDAC inhibitor resminostat in sorafenib-refractory hepatocellular carcinoma (HCC): Phase II SHELTER study.

Abstract

4115 Background: Resminostat (R), an oral HDAC inhibitor, was studied in the SHELTER trial evaluating safety, PK and efficacy in HCC patients (pts) refractory to sorafenib (S). R was explored as monotherapy and within a novel resensitization approach to overcome tolerance to S by the combination of both drugs. Methods: Pts with advanced HCC (BCLC B/C) were included in a multi-center, two-arm trial. Radiologic progression under S firstline therapy had to be confirmed by central review (RECIST) prior to study entry. A dose escalation of R (range 200 to 600 mg) combined with S (400 or 800 mg) was performed. Arm A investigated the drug combination (R+S), Arm B the monotherapy of R (600 mg). Primary objective was the progression-free survival rate (PFSR) after 12 weeks (w). Secondary objectives included safety, tolerability, tumor response, PFS, TTP, OS and the analyses of PK and biomarkers (BM), incl. AFP, VEGF, HDAC enzyme inhibition, histone acetylation and gene expressions in peripheral blood. Results: 50 pts were enrolled, dose escalation determined 600 mg R and 400 mg S for Arm A. Clinical activity results of 15 evaluable pts from combination treatment revealing a PFSR of 66.6% after 12 w, not all patients in Arm B already reached the 12 w staging. Most frequent AE were CTC grade 1-2 GI complaints (nausea, vomiting) and skin disorders (rash, pruritus, HFSR). Grade 3-4 toxicity (SAE reports) consisted mainly of non-hematological events mostly related to tumor disease. Plasma concentrations of both drugs correlated with administered doses and were in the expected range without obvious influence of preexisting liver disease. BM investigations revealed effective target modulation by R in both arms. Conclusions: The primary study objective was achieved for both treatment arms. R demonstrated a favorable PK, safety and tolerability profile, even in combination with S and despite preexisting liver disease, includig cirrhosis. The observed clinical activity emphazises the resensitizing activity of R by an epigenetic mode-of-action to overcome tolerance to S and warrants further development, in particular for combination therapy in both, first and second line HCC treatment.