Abstract 1171: Urinary excretion of rigosertib (ON 01910.Na), a novel synthetic benzylstyrylsulfone, in a phase I trial.
Authors: Cho Sool Y. , Roboz John , Ohnuma Takao 
Published: August 2014

Abstract
Rigosertib (ON 01910.Na, MW 473.5 Da), a novel synthetic benzylstyrylsulfone, was given to 27 patients with solid tumors in a Phase I clinical trial. Drug doses were 50 to 1,700 mg/m2/24 h x 3 days, continuously infused for 72 h (one cycle), repeated every 2 weeks. The drug was generally well tolerated. In isolated cases severe toxicities, including neuromuscular changes, small bowel obstruction and hyponatremia, were encountered. Urine samples were collected from 14 patients. For 12 patients, urine was collected only in the first cycle with the following doses: 400 mg/m2 - 2 patients, 850 mg/m2 - 1 patient, 1,050 mg/m2 - 3 patients, 1,375 mg/m2 - 5 patients, 1,700 mg/m2 - 1 patient. For two patients, urine was collected both in the 1st and 4th cycle: 1 patient with 325 mg/m2 in both cycles, and another patient, with 850 mg/m2 in the first cycle, and 1,050 mg/m2 in the fourth cycle. Urine collection periods were 0-4 h, 4-8 h, 8-24 h, 24-48 h, 48-72 h (end of infusion), 72- 96 h and 96-120 h (post-infusion). Urine was collected in 4 L bottles (volume recorded) and alkalinized with sodium bicarbonate to pH 8.0-9.0; 50 mL fractions were frozen at -80 °C, until analysis. Liquid chromatography-electrospray-mass spectrometry was used with selected reaction monitoring (SRM) of m/z transition from 474 to 216 for rigosertib and from m/z 379 to 120 for the internal standard (ON 01370, an analog compound, MW 378.4 Da). Transition of m/z from 394 to 162 was monitored to determine a possible metabolite (ON 01500, the parent compound). Urinary excretion of rigosertib was rapid in all patients, and ceased soon after the end of infusion. There were no cumulative effects in repeated collections in the fourth cycle. In terms of total drug recovered, the urinary excretion averaged 3.0% (0%-15%) in the 72-96 h collection interval and 0.14% (0-0.56%) in the 96-120 h interval. These results suggest that most drug excreted by 72 h. The amount of drug excreted ranged 3% to 15% of the total administered. Among 16 sets of urine samples (from 14 patients, including 2 patients with 2 sets each), at the dose of 325-400 mg/m2 (n=4) the level of urinary excretion ranged 3-9%; drug excretion was 8-15% at 850-1,050 mg/m2 (n=6), and at 1,375-1,700 mg/m2 levels the excretion was 7-15 % (n=6). Clinical toxicities did not appear to have influenced urinary excretion patterns. No significant amount of ON 01500 (a possible metabolite) was found in any urine sample examined; the detection limit was ≤ 10 ng/mL. These results are consistent with and complementary to previous reports: strong (up to 98%) protein binding of rigosertib in human plasma (Cancer Chemother. Pharmacol. 65:177, 2009), and discontinuous albumin binding of the drug (Drug Metab. Dispos. 38:1480, 2010), suggesting that high protein binding of rigosertib likely have influenced active tubular absorption and resulted in low levels of urinary excretion.
Citation Format: Sool Y. Cho, John Roboz, Takao Ohnuma. Urinary excretion of rigosertib (ON 01910.Na), a novel synthetic benzylstyrylsulfone, in a phase I trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1171. doi:10.1158/1538-7445.AM2013-1171