Phase I clinical, pharmacokinetic and pharmacodynamic study of SB939, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumours.

BACKGROUND: SB939 is an orally available, competitive histone deacetylase (HDAC) inhibitor selective for class I, II and IV histone deacetylases. Preclinical evaluation of SB939 revealed a profile suggesting improved efficacy compared to other HDAC inhibitors. This phase I study was carried out to determine the safety, dose-limiting toxicity, recommended phase II dose (RPTD), as well as pharmacokinetic (PK) and pharmacodynamic (PD) profiles of SB939 in a daily × 5 schedule in advanced solid tumours. METHODS: Sequential dose-escalating cohorts of patients were enrolled into 8 dose levels. At dose level 1, SB939 was taken on days 1-3 and 15-17 every 4 weeks, then on days 1-5 and 15-19 for other dose levels. Detailed PK sampling was performed in cycle 1, days 1 and 5. Peripheral blood mononuclear cells (PBMCs) were collected on cycle 1 at various time points for determination of acetylated histone H3 (AcH3) levels. RESULTS: In total, 38 patients received a total of 96 cycles of treatment. The maximal administered dose was 90 mg and the RPTD was 60 mg given 5 consecutive days every 2 weeks. The most frequent non-hematologic adverse events (AEs) of at least possible attribution to SB939 were fatigue, nausea, vomiting, anorexia and diarrhoea. Pharmacokinetic analysis showed dose-proportional increases in AUC across the doses evaluated. Elimination half-life was 5.6-8.9 h. There was no clear relationship between AcH3 changes and dose level or anti-tumour response. CONCLUSIONS: SB939 is well tolerated in patients with advanced solid tumours. The RPTD of this drug is 60 mg on a schedule of 5 consecutive days every 2 weeks. The toxicities of SB939 are consistent with other HDAC inhibitors.