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

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.

• Authors: André T Brunetto, Joo Ern Ang, Rohit Lal, David Olmos, L Rhoda Molife, Rebecca Kristeleit, Ann Parker, Isabel Casamayor, Muyibat Olaleye, Anna Mais, Bernhard Hauns, Vera Strobel, Bernd Hentsch, Johann S de Bono
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 19 Pg. 5494-504 (Oct 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 24065624 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• Histones
• Hydroxamic Acids
• Sulfonamides
• resminostat

Topics

• Acetylation
• Administration, Oral
• Adult
• Aged
• Antineoplastic Agents
• Drug Administration Schedule
• Female
• Histone Deacetylase Inhibitors
• Histones (metabolism)
• Humans
• Hydroxamic Acids (adverse effects, pharmacology, therapeutic use)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Staging
• Neoplasms (diagnosis, drug therapy)
• Sulfonamides (adverse effects, pharmacology, therapeutic use)
• Treatment Outcome