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Clin Cancer Res. 2013 Oct 1;19(19):5494-504. doi: 10.1158/1078-0432.CCR-13-0735. Epub 2013 Sep 24.

First-in-human, pharmacokinetic and pharmacodynamic phase I study of Resminostat, an oral histone deacetylase inhibitor, in patients with advanced solid tumors.

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1
Authors' Affiliations: Drug Development Unit, Divisions of Cancer Therapeutics & Clinical Studies, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom; and 4SC AG, Planegg-Martinsried, Germany.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

RESULTS:

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.

CONCLUSIONS:

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.

PMID:
24065624
PMCID:
PMC3790647
DOI:
10.1158/1078-0432.CCR-13-0735
[Indexed for MEDLINE]
Free PMC Article

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