A phase I study to assess oral bioavailability of a novel oral soft gelatin capsule formulation of rigosertib (ON 01910.Na) under fasted and fed conditions in patients with myelodysplastic syndromes.

Abstract

3081 Background: Rigosertib (ON 01910.Na) is a novel multikinase inhibitor, with selective cytotoxic effects on tumor cells without impact on normal cells. Rigosertib, administered as a 3-day continuous infusion, is now undergoing phase 3 evaluation in higher risk MDS patients refractory to hypomethylating agents. Here, we report the results of the effect of food on the absolute bioavailability of a novel rigosertib oral formulation (soft gelatin capsule) in MDS patients. Methods: This was a single-dose, three-treatment, three-period sequential design for studying the effects of food on the bioavailability of an immediate-release soft gelatin capsule formulation. The following dosing groups were tested in 12 patients: IV Dose 800 mg/m2 over 24 hours and oral dose 560 mg (2 x 280 mg capsules) under fasting and fed conditions. The oral dose was the recommended phase 2 dose, as reported previously (R.S. Komrokji et al., Oral Formulation of Rigosertib (ON 01910.Na) in Patients with Myelodysplastic Syndrome (MDS) – Phase I Study Results. Blood 2011, 118:Abstract #3797). Plasma samples were collected pre-dose, and over 32 hours (IV dose) or 8 hours (oral dose) after dose initiation. Rigosertib plasma levels were analyzed by a validated LC/MS/MS method. Pharmacokinetic parameters were estimated by noncompartmental analysis (WinNonlinÒ). Results: Rigosertib pharmacokinetic parameters are presented in the table below. The results of the present study demonstrate good oral bioavailability under fasting condition.Oral administration of rigosertib after a meal decreased Cmax and AUC by 77% and 61%, respectively, compared to fasting conditions. Conclusions: The results of this study support the potential for oral delivery of rigosertib, which could become a preferred therapy over a 3-day continuous intravenous infusion. [Table: see text]