Multicenter, Open-Label Phase I Clinical Study of Oral Rigosertib in Japanese Patients with Recurrent/Relapsed or Refractory Myelodysplastic Syndromes: Tolerability, Efficacy, and Pharmacokinetic Profiles
Authors: Ishizawa Kenichi , Usuki Kensuke , Ando Kiyoshi , Ueda Yasunori , Kiguchi Toru , Uike Naokuni , Onishi Yasushi , Iida Hiroatsu 
Published: October 2019

Abstract
Background:Rigosertib is a novel phosphoinositide 3 kinase pathway inhibitor that induces G2/M arrest leading to the apoptosis of cancer cells and myeloblasts and causes minimal damage to normal cells. A Phase I study in the U.S. showed the safety and good tolerability of oral rigosertib in patients (pts) with low, intermediate-1, intermediate-2, or high risk myelodysplastic syndromes (MDS).
Methods:A multicenter, open-label Phase I clinical study was conducted to examine the tolerability of oral rigosertib in Japanese pts with recurrent/relapsed or refractory MDS, and to determine the recommended dose for a Phase II clinical study. The key eligibility criteria were as follows: patients with recurrent/relapsed or refractory MDS, aged 20 years or older, ECOG PS of 0 to 2, and no major organ dysfunctions. Rigosertib (280 and 560 mg BID) was administered orally in one 21-day cycle that consisted of the 14-day, twice-daily, oral administration term, followed by the 7-day monitoring term. In principle, oral rigosertib was administered in up to cycle 6. The primary endpoint was the dose-limiting toxicity (DLT) in each dose group. The secondary endpoints were as follows: 1) safety as assessed with adverse events (AEs) and laboratory results; 2) efficacy as assessed according to the International Working Group 2006 criteria; and 3) pharmacokinetics.
Results: Between March 2013 and November 2014, 10 patients were enrolled at 7 medical institutions in Japan. However, 1 of them did not receive rigosertib because of a tendency for PS deterioration. Six pts were male, the median age was 70 years (range 52 to 80 years), and ECOG PS was 0 in 7 pts and was 1 in 2 pts. Consequently, 3 and 6 pts were eventually assigned to the 280 and 560 mg dose groups, respectively. According to the FAB classification, 4, 2, 2, and 1 pts were categorized to RAEB, RARS, RA, and RAEB-t, respectively. The prognostic factor according to IPSS was Int-1 risk in 4 pts (1 and 3 pts in the 280 and 560 mg dose groups, respectively) and was Int-2 in 5 pts (2 and 3 pts in the 280 and 560 mg dose groups, respectively). In the 280 mg dose group, 2 of 3 pts completed cycle 6, and the median relative dose intensity (RDI) was 86% (77 to 92%). In the 560 mg dose group, the maximum number of cycles delivered was 4, and the median RDI was 85% (68 to 93%). A total of 57 AEs developed. In the 280 mg dose group, grade 3 or higher nonhematologic toxicities, grade 3 type 2 diabetes mellitus, and grade 4 delirium (1/3, 33.3%) developed. In the 560 mg dose group, grade 3 AEs: cholecystitis, periodontitis, pneumonia, soft tissue infection, increased alanine aminotransferase, increased aspartate aminotransferase, and prolonged QT interval, as well as grade 5 urinary tract infection (1/6, 16.7%) developed. DLTs (all of which were grade 3 or higher nonhematologic toxicities) were observed with 1 of 3 pts in the 280 mg dose group (type 2 diabetes mellitus and delirium) and with 2 of 6 pts in the 560 mg dose group (urinary tract infection and prolonged QT interval). Serious AEs were 2 events in 1 of 3 pts in the 280 mg dose group (type 2 diabetes mellitus and delirium) and were 6 events in 3 of 6 pts in the 560 mg dose group (soft tissue infection, periodontitis, cholecystitis, and pneumonia in 1 pt, hematuria in 1 pt, and urinary tract infection in 1 pt). One pt in the 560 mg dose group died of septic shock that had been caused by a urinary tract infection during the study period. The hematological remission rate was 11.1% (1 marrow CR; 1/9 pts), and the hematological improvement rate was 11.1% (1 HI-P; 1/9 pts); however, cytogenetic response was not found. Plasma concentrations of rigosertib increased rapidly after each oral administration. Among the PK parameters, intersubject variability was observed in the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC). However, changes suggesting the accumulation of rigosertib during repeated oral administration (e.g., consistent increases in the Cmax and AUC) were not found. The urinary excretion rates of rigosertib on day 1 were 1.6 ± 1.0% and 11.0 ± 6.6% (mean ± SD) in the 280 and 560 mg dose groups, respectively.
Conclusions: The present chemotherapy regimen of oral rigosertib was well tolerated. Our study indicates that the recommended dose for a Phase II clinical study is 560 mg BID in Japanese patients with recurrent/relapsed or refractory MDS.

Disclosures
Ishizawa: SymBio Pharmaceuticals: Research Funding. Usuki:Nippon Shinyaku: Honoraria; Sumitomo Dainippon Pharma: Honoraria; MSD: Honoraria; Kyouwa-Kirin: Honoraria; Novartis: Honoraria; Bristol-Myer-Squibb: Honoraria; SymBio Pharmaceuticals: Research Funding. Ando:SymBio Pharmaceuticals: Research Funding. Ueda:SymBio Pharmaceuticals: Research Funding. Uike:SymBio Pharmaceuticals: Research Funding. Onishi:SymBio Pharmaceuticals: Research Funding. Iida:SymBio Pharmaceuticals: Research Funding.