Resminostat and sorafenib combination therapy for advanced hepatocellular carcinoma in patients previously untreated with systemic chemotherapy.

Abstract

252 Background: Resminostat is an oral hydroxamate-type inhibitor of class I, IIB, and IV histone deacetylases. A European Phase II study of second-line combination therapy with resminostat and sorafenib for hepatocellular carcinoma (HCC) in patients (pts) revealed a promising improvement in overall survival (OS). Here we report the findings on safety and efficacy of an Asian Phase I/II study on first-line combination therapy with sorafenib and resminostat in HCC pts. Methods: Pts with advanced or metastatic HCC considered Child-Pugh A and ECOG 0/1 were enrolled in Japan and Korea. Sorafenib was administered at 400 mg (bid) in both Phase I and II. Resminostat was administered on days 1 to 5 every 14 days. In Phase I, the dose of resminostat was escalated from 400 mg/day (DL1) to 600 mg/day (DL2). In Phase II, pts were randomly assigned to sorafenib monotherapy or sorafenib/resminostat combination therapy at a ratio of 1:1. The primary endpoint was time to progression (TTP). Tumor response was assessed according to RECIST version 1.1 every 6 weeks. Results: A total of 9 pts were enrolled in Phase I (DL1, 3 pts; DL2, 6 pts). Higher incidences of G3-4 toxicities, including one DLT (G4 thrombocytopenia), were observed at DL2. Therefore, DL1 was determined as the recommended dose for Phase II. A total of 170 pts were enrolled in Phase II. The median TTP was 2.8 months in the combination and control arm, respectively (HR: 0.984). No significant difference was observed in the median OS. Retrospective analysis revealed favorable results for the combination option in certain subgroups: for example, HBV+ (TTP: HR, 0.630; OS: HR, 0.846); no prior therapy (TTP: HR, 0.629; OS: HR, 0.590); and platelet count > = 151.000 (TTP: HR, 0.646; OS: HR, 0.509). Conclusions: Although the primary endpoint was not reached in this Phase II all-comer HCC study, the results of the subgroup analysis suggest a population-specific effect for the combination therapy, especially in one which is HBV+. This warrants the further development of this combination as first-line therapy in a well-defined subset of pts with advanced HCC. Clinical trial information: NCT02400788.

Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends

“…Another HDAC inhibitor, romidepsin [ 67 ] belonging to the family of depsipeptide natural products was approved for CTCL. Sipruchostatin, also belonging to the class of natural product depsipeptide is currently undergoing phase 1 clinical investigation for the treatment of solid tumors [ 198 , 199 ]. Belinostat (PXD-101) that bears a more rigid alkenyl hydroxamic acid is the third HDAC inhibitor to be approved by US FDA in 2014 [ 69 ] for the treatment of PTCL.…”

“…In phase II study, 170 pts were enrolled and the results demonstrated a median time to progression of 2.8 months in the combination and control arm. Significant difference was not observed in the median OS (NCT02400788) [ 199 ] Resminostat was also tested in R/R HL in a phase 2 study and the results demonstrated clear OR in R/R HL patients. Moreover, the drug was found to be endowed with excellent safety profiles in heavily pre-treated patient population (NCT01037478) [ 200 ] In a phase I/II study conducted in japanese patients with stage IIIB/IV or recurrent NSCLC and prior platinum-based chemotherapy, no DLT was observed in phase I part and the recommended dose was determined to be 600 mg/day with 75 mg/m 2 of docetaxel.…”

“…Another alkenyl type small molecule HDAC inhibitor, Panobinostat, received FDA approval in 2015 for the treatment of patients with multiple myeloma [70]. The FDA approvals of belinostat and panobinostat opened an avenue for the exploration of alkenyl type drug candidates and subsequently, resminostat [199][200][201][202] and pracinostat [203][204][205] were identified that are now undergoing clinical stage investigation. Givinostat [206][207][208], abexinostat [209,210], AR-42 [211,212] and bisthianostat [213,214] represents the chemically related compounds bearing a more rigid phenylhydroxamic acid while quisinostat [215][216][217], nanatinostat [218,219] and fimepinostat [220] containing a more polar pyrimidinyl heteroaromatic EED-EZH2 protein-protein interaction (PPI) disruption leads to loss of H3K27me3-stimulated PRC2 activity and prevents H3K27 trimethylation, which ultimately leads to decreased tumor cell proliferation in EZH2-mutated and PRC2-dependent cancer cells.…”

“…In phase II study, 170 pts were enrolled and the results demonstrated a median time to progression of 2.8 months in the combination and control arm. Significant difference was not observed in the median OS (NCT02400788) [199] Resminostat was also tested in R/R HL in a phase 2 study and the results demonstrated clear OR in R/R HL patients.…”

Dual Acting Polymeric Nano-Aggregates for Liver Cancer Therapy

“…Current treatment regimens often are not effective because of the late stage of diagnosis and the inability to deliver the correct therapeutic dose to the liver [2]. Over the past few years, more effort has been concentrated in the development of multifunctional [3,4,5] or combination therapy [6,7,8] in order to improve existing anticancer treatments. This strategy has previously identified that combination therapy can result in synergy and overall can improve efficacy of therapies, as well as reduced drug resistance.…”