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

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 (C_max) 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 C_max 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.