Abstract 114: Mass balance study of 14C- belinostat in patients with recurrent or progressive malignancy

Abstract

Abstract Background: Belinostat is a hydroxamic acid based pan-histone deacetylase (HDAC) inhibitor that inhibits Class I, II, and IV HDAC enzymes at micromolar concentrations; it (Beleodaq) was recently approved in the US for the treatment of relapsed/refractory PTCL. The excretion of belinostat and its metabolites has been studied using radiolabeled belinostat in dogs and rats (∼70% and 50% excreted fecally and 30% and 50% excreted renally, respectively). The renal excretion of parent belinostat was <1% in both species. Objective: To determine the excretion route of radiolabeled belinostat and its metabolites following single IV administration of 14C-labeled belinostat in patients with advanced cancers. Secondary objectives included an assessment of safety. Methods: Patients with progressive or recurrent malignancies who failed standard therapies were eligible for the study. Patients with severe constipation, urinary incontinence, primary hepatic or renal carcinomas were excluded. Six eligible patients received a single dose of 14 C-labeled belinostat (approximately 90 to 105 μCi, 1500 mg) as a 30-minute IV infusion. Blood, urine, and fecal samples were collected at pre-determined time points (up to 168 hours) for measurement of total radioactivity. Results: Six patients with a median age of 66 yrs (range: 55 to 75) were enrolled. Total recoveries of radiolabeled material ranged from 87.6% to 97.9% (mean 94.5% ± 4.0%). The majority of the excreted belinostat dose in urine was recovered within 48 hours (83.8%) with only 9.3% in the feces within 96 hours. Renal elimination was the principal route of excretion of radioactivity in all patients, representing a mean of 84.8% ± 9.8% of the administered dose. Fecal excretion accounted for only 9.7% ± 6.5% of the administered dose. Belinostat was shown to be extensively metabolized. The parent compound accounted for only ∼10% of the total drug exposure and was below the level of detection in plasma samples taken 4.5 hours post-dose. Belinostat glucuronide was the major circulating plasma metabolite accounting for ∼65% of the total drug exposure with urinary excretion as the major route of elimination. Belinostat glucuronide was the predominant urinary metabolite accounting for 36% of the total administered dose. Belinostat amide was the most abundant metabolite in feces, accounting for 6% of the total administered radioactivity. The most commonly treatment-related adverse events were Grade 1-2 nausea (50%), infusion site pain (50%) and fatigue (33%). Conclusion: In this study, mass balance was achieved with a mean recovery of 94% radiolabeled belinostat. Belinostat was shown to be extensively metabolized with parent compound accounting for only about 10% of the excreted radiolabeled material and radiolabeled material was primarily excreted by the renal route. Belinostat glucuronide is the primary circulating metabolite and the primary metabolite excreted in the urine. Citation Format: Emiliano Calvo, Valentian Boni, Lina Garcia Canamaque, Guru Reddy, Jette Tjornelund, Tao Song, Mi Rim Choi, Lee F. Allen. Mass balance study of 14C- belinostat in patients with recurrent or progressive malignancy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 114. doi:10.1158/1538-7445.AM2015-114