P-0082 Dose Escalation of the HDAC Inhibitor Resminostat in Combination Treatment with Sorafenib in Patients with Hepatocellular Carcinoma

Introduction Resminostat (R), a newly developed pan-HDAC inhibitor, is currently under clinical investigation in various oncological indications. The phase I part of the SHELTER study was aimed to evaluate safety, tolerability, pharmacokinetics (PK) and efficacy of resminostat in combination with the multi-kinase inhibitor sorafenib in a dose-escalating, multiple dose design. The rationale of combining an epigenetic and targeted treatment approach was to clinically explore its ability of tumor resensitization and inversion of the refractory status to sorafenib in HCC patients (pts) exhibiting progressive disease under first-line therapy. Methods Pts with advanced HCC (BCLC B or C) were included in a multi-center, open-label, two-arm parallel group trial. Radiological progression under sorafenib was determined acc. to RECIST by central review prior to study inclusion. In the phase I part, a dose escalation of resminostat and sorafenib was performed to determine dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of the combination. Resminostat was administered orally once-daily during 5 consecutive days followed by a 9-day rest period resulting in 14 day treatment cycles, whereas sorafenib was given continuously. Study objectives included safety and tolerability, tumor response, PFS, TTP, OS, PK, and surrogate markers. Results Dose escalation started from dose level DL1 (R 200 mg, 3 pts), to DL2 (R 400 mg, 3 pts), and DL3+4 (R 600 mg, 6 pts each), either combined with sorafenib 400 mg TDD on DL1-3 or 800 mg TDD on DL4 given orally twice-daily. No intra-individual dose escalation was performed. A single DLT (QTc interval prolongation, CTC grade 3) occurred at DL3, therefore 3 additional pts were enrolled. At DL4, no DLT was detected in 6 pts included, thus a formal MTD could not be determined. Most frequently observed adverse events included CTC grade 1-2 gastrointestinal complaints including nausea and vomiting and skin disorders like rash, pruritus and hand-foot skin reaction. CTC Grade 3-4 toxicity documented in SAE reports consisted mainly of non-hematological events and was mostly related to the underlying malignant disease. PK analyses revealed consistency with the known PK profiles of both substances without obvious influence of pre-existing liver disease. No PK outlier for resminostat or sorafenib was detected. Importantly, no trends for drug accumulation that could have led to either limited tolerability of the treatment or safety concerns were observed. Central ECG evaluation did not reveal signals of drug-induced cardiac toxicity. Seven of 18 pts (39%) in the dose escalation phase revealed stable disease after 12-week staging in local assessment; one patient included at DL3 is under treatment for more than 1.5 years as of today. Conclusion Phase I data of the SHELTER trial substantially support further clinical development of the HDAC inhibitor resminostat as combination partner with sorafenib. Up to the highest dose level of 600 mg resminostat OD and 400 mg sorafenib BID, treatment was generally well tolerated and manageable. A formal MTD was not established. Based on these data, the efficacy of the combination of resminostat and sorafenib has been further investigated in stage II of the trial.