Evaluation of Rigosertib in Patients with a Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML) Relapsed or Refractory to Hypomethylating Agents: A Phase I/II Study

Rigosertib is a small molecule anti-cancer agent with a multi-targeted mechanism of action. It is a multi-kinase/PI3 kinase inhibitor that promotes G2/M arrest and selectively induces apoptosis in cancer cells. Leukemic cells exhibit significantly higher levels of sensitivity to rigosertib compared to normal marrow progenitors and increasing cytotoxicity upon prolonged and repetitive exposure (Chen Proc AACR 2008). Azacitidine is first-line therapy for patients (pts) with higher-risk MDS and produces a response rate of 50%. Pts relapsed or refractory to hypomethylating agents have a short life expectancy of approximately 4 to 6 months (Jabbour 2010, Prebet 2011). There are no approved second line therapies for this patient population.

A phase I/II study of Rigosertib is being conducted in pts with MDS and AML. Pts with higher-risk disease had to have failed a hypomethylating agent. In the phase I component, pts were entered in cohorts of escalating doses in a classic 3+3 design ranging from 650 up to 1700 mg/m²/d continuous IV infusion (CIV) for durations from 72 hours to 144 hours every 2 weeks (1 cycle) for 4 cycles of treatment during the induction phase. Subsequent treatments were administered every 3 to 4 weeks. A maximum tolerated dose of 1375 mg/m² was identified for the phase II component, and subsequent pts were treated with this dose as a CIV for 72 hours. A CBC was performed weekly and a bone marrow (BM) was performed at baseline and week 4, 8, and then q3 months afterwards.

Twenty-one patients with MDS or AML refractory/relapsed to a hypomethylating agent have been treated with rigosertib. The study cohort comprised pts with a diagnosis of intermediate-2 MDS (2 pts), high risk MDS (5 pts), chronic myelomonocytic leukemia (1 pt), and AML (13 pts) (all AML had an antecedent MDS). The median age was 79 years. 86% of pts were male. Patients received between 1–19 cycles of treatment. Their cytogenetic profiles were diverse with the most recurrent abnormalities including a complex karyotype (5 pts), normal (5 pts), monosomy 7 (4 pts), and trisomy 8 (2 pts). Responses according to IWG 2006 criteria were observed in the BM and peripheral blood: marrow CR (4), hematologic improvement (HI) (2); erythroid (1) platelet (1). Time to response was 2–4 cycles. An additional 2 pts had a >50% BM blast decrease from baseline but not to < 5%. Three pts had stable disease after treatment but their courses were complicated by infections requiring hospitalization and removal from the study. Three pts were deemed to be inevaluable because they received less than 2 cycles of treatment or did not have a follow-up bone marrow evaluation. Thus, 9/18 evaluable pts (50%) demonstrated either a bone marrow/peripheral blood response (6) or stable disease (3). The median overall survival of those with marrow CR+PR was 10.1 months versus 2 months for those without a bone marrow response (p=0.0011, log-rank test). Of those pts who did not respond or were inevaluable, the majority (83%) had AML, many with a proliferative course. The most frequent grade 1–2 side-effects included dysuria, hematuria, fatigue, anorexia, nausea, and diarrhea. Possibly related grade 3 side-effects included fatigue, hematuria, and dyspnea, each in one pt. Six of 21 pts developed cystitis manifested by dysuria and/or hematuria. Among responding or stable patients, 5 of 9 had cystitis compared with 1 of 12 non-responders. Patients who developed symptomatic cystitis were treated with sodium bicarbonate with improvement. The relationship between dysuria and/or cystitis and response is being investigated.

Rigosertib appears to be safe and well tolerated in patients with refractory or relapsed MDS and AML. It has biologic activity with reduction in BM blasts and improvement in the peripheral blood counts in a subset of treated pts, and these effects are associated with increased survival. Dysuria/cystitis may be a response related biomarker and requires further analysis. Data regarding pharmacokinetics and pharmacodynamics will be presented and correlated to response. Given promising initial results, a phase III multicenter randomized trial is underway to compare rigosertib to best supportive care with a primary endpoint of overall survival in patients with higher risk MDS who have failed, progressed, or relapsed after treatment with hypomethylating agents.

Reddy:Onconova: Research Funding. Holland:Onconova: Research Funding. Wilhelm:Onconova: Employment, Equity Ownership. Silverman:Onconova: Research Funding.