resminostat and Neoplasms

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.. 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.. 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.. 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.

Topics: Adult; Aged; Asian People; Drug Administration Schedule; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Sulfonamides

This first-in-human dose-escalating trial investigated the safety, tolerability, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of the novel histone deacetylase (HDAC) inhibitor resminostat in patients with advanced solid tumors.. Resminostat was administered orally once-daily on days 1 to 5 every 14 days at 5 dose levels between 100 and 800 mg. Safety, pharmacokinetics, pharmacodynamics including histone acetylation and HDAC enzyme activity, and antitumor efficacy were assessed.. Nineteen patients (median age 58 years, range 39-70) were treated. At 800 mg, 1 patient experienced grade 3 nausea and vomiting, grade 2 liver enzyme elevation, and grade 1 hypokalemia and thrombocytopenia; these were declared as a combined DLT. No other DLT was observed. Although an MTD was not reached and patients were safely dosed up to 800 mg, 3 of 7 patients treated with 800 mg underwent dose reductions after the DLT-defining period due to cumulative gastrointestinal toxicities and fatigue. All toxicities resolved following drug cessation. No grade 4 treatment-related adverse event was observed. The pharmacokinetic profile was dose-proportional with low inter-patient variability. Pharmacodynamic inhibition of HDAC enzyme was dose-dependent and reached 100% at doses ≥400 mg. Eleven heavily pretreated patients had stable disease and 1 patient with metastatic thymoma had a 27% reduction in target lesion dimensions.. Resminostat was safely administered with a dose-proportional pharmacokinetic profile, optimal on-target pharmacodynamic activity at dose levels ≥400 mg and signs of antitumor efficacy. The recommended phase II dose is 600 mg once-daily on days 1 to 5 every 14 days.

Topics: Acetylation; Administration, Oral; Adult; Aged; Antineoplastic Agents; Drug Administration Schedule; Female; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Sulfonamides; Treatment Outcome