A phase I study of resminostat in Japanese patients with advanced solid tumors

Abstract

Purpose: This study was performed to evaluate the safety and determine the recommended dose (RD) of resminostat monotherapy, an oral histone deacetylase (HDAC) inhibitor, in Japanese patients with advanced solid tumors.

Methods: Resminostat was administered to patients with advanced solid tumors on a 14-day cycle consisting of once-daily administration on days 1-5. The dose was initiated at 400 mg and increased to 600 mg and then 800 mg. Treatment with resminostat was continued until disease progression or discontinuation for any other reason. Dose-limiting toxicities (DLTs) were assessed according to the adverse drug reactions occurring in the first cycle. Secondary objectives included the pharmacokinetics, pharmacodynamics, and efficacy.

Results: A total of 12 patients were enrolled in the study and received resminostat. No DLTs were reported in any patient. The maximum tolerated dose was not reached. Frequently reported grade 3/4 adverse drug reactions were as follows: lymphocytopenia (33.3 %), thrombocytopenia (25.0 %), neutropenia (16.7 %), and leukocytopenia (16.7 %). Pharmacokinetic analysis revealed that there was no accumulation of the drug over the 5-day administration period and no significant difference in pharmacokinetic parameters between the single dose and multiple doses. Measurement of acetylated H4 histone protein levels in peripheral blood mononuclear cells demonstrated that resminostat inhibited HDAC activity at all the doses assessed. No patients had a complete or partial response, whereas three patients had stable disease.

Conclusions: Resminostat was safely administered to Japanese patients with advanced solid tumors. The RD of resminostat monotherapy in Japanese patients was estimated to be 800 mg.