Safety, Efficacy, and Pharmacokinetic Profiles of Intravenous Rigosertib in Japanese Patients with Recurrent/Relapsed or Refractory Myelodysplastic Syndromes: A Multicenter, Open-Label Phase I Clinical Study

Background and Objectives: Rigosertib, a novel phosphoinositide 3/polo-like kinase pathway inhibitor, promotes G2/M arrest, selectively induces the apoptosis of cancer cells, and has no impact on normal cells. A Phase I/II study in the U.S. showed that rigosertib was safe and well tolerated in patients (pts) with myelodysplastic syndromes (MDS) or acute myeloid leukemia relapsed after or refractory to treatment with hypomethylating agents. A multicenter, open-label Phase I dose-finding study of rigosertib was conducted to evaluate the safety and preliminary efficacy, and to determine the recommended dose for a Phase II study in Japanese patients with recurrent/relapsed or refractory MDS.

Patients and Methods: The key eligibility criteria were as follows: patients withrecurrent/relapsed or refractory MDS; FAB classifications (RA, RARS, RAEB, RABE-t, and CMML), excepting patients at IPSS low- or Int-1 risk with respect to RA; aged 20 years or older, ECOG PS of 0 to 2, no major organ dysfunctions, and written informed consent. Rigosertib (1,200 and 1,800 mg daily) was administered intravenously in one 14-day cycle that consisted of continuous intravenous administration for 72 hours followed by monitoring for 14 days. In principle, intravenous rigosertib was administered in up to cycle 8. The primary endpoint was the dose-limiting toxicity (DLT) in each cohort. The secondary endpoints were as follows: 1) safety as assessed with adverse events (AEs) and laboratory results; 2) the hematological remission rate, the hematological improvement rate, and the cytogenetic response rate¾all of which were assessed according to the International Working Group 2006 criteria; and 3) pharmacokinetics.

Results: Between June 2012 and February 2015, a total of 9 pts with a median age of 70 (range: 63 to 84) years and with a 7/2 ratio of male/female were enrolled from 5 medical institutions in Japan, and 3 and 6 pts were eventually assigned to the 1,200 and 1,800 mg cohorts, respectively. According to the FAB classification, 6, 2, and 1 pts were categorized to RAEB, RAEB-t, and RA, respectively. There were 3 pts each in the IPSS Int-1, Int-2, and high-risk risk groups, with 1 and 2 pts in each risk group in the 1,200 and 1,800 mg cohorts, respectively. The median numbers of delivered cycles in the 1,200 and 1,800 mg cohorts were 4 (2 to 4) and 2 (1 to 8), respectively. The median relative dose intensity (RDI) in the 1,200 and 1,800 mg cohorts was 100% (98.2 to 100.0%) and 79% (55.6-100%), respectively; lower RDI in the 1,800 mg cohort was caused by dose delay in the next treatment due to toxicities. A total of 169 AEs developed. The most frequently observed grade 4 hematologic toxicities included neutropenia (3/9, 33%), thrombocytopenia (3/9, 33%), and leukopenia (3/9, 33%). Grade 3 or greater non-hematologic toxicities included grade 4 meningitis (1/9, 11%), grade 4 sepsis (1/9, 11%), grade 3 catheter-related infections (2/9, 22%), grade 3 hyponatremia (2/9, 22%), and grade 3 anorexia (2/9, 22%). DLT was not observed in the 1,200 mg cohort, while 2 pts in the 1,800 mg cohort had 5 DLTs (sepsis and meningitis in one pt, as well as hyponatremia, pustular rash, and hypochloremia in the other pt). Three serious AEs, including grade 4 meningitis, grade 4 sepsis, and grade 3 catheter-related infection, developed in the 1,800 mg cohort. No death occurred during the study period. Stable disease was obtained in 2 pts in the 1,800 mg cohort. Any hematological remission, hematological improvement, and cytogenetic response were not obtained in the two cohorts. In the 1,200 mg cohort, maximum plasma concentration (C_max) was 5.99 ± 1.50 μg/mL (mean ± SD), and the area under the concentration-time curve (AUC_0-∞) was 314.6 ± 142.7 μgŸ・hr/mL. In the 1,800 mg cohort, the C_max was 6.74 ± 2.39 μg/mL, and the AUC_0-∞ was 324.8 ± 83.9 μgŸ・hr/mL. The urinary excretion rates of rigosertib in the 1,200 and 1,800 mg cohorts were 12.7 ± 6.6% and 16.2 ± 4.7%, respectively.

Conclusions: This Phase I study showed that intravenous rigosertib of 1,800 mg daily for 72 hours was well tolerated, although remarkable efficacy was not observed. The recommended dose for Japanese patients was determined to be 1,800 mg daily for 3 consecutive days as with a Phase III study in the U.S. Based on these data, Japanese MDS patients started to participate in a global randomized Phase III study to compare rigosertib vs. physicians' choice of treatment.