Azacitidine is the standard of care for higher risk myelodysplastic syndromes (MDS); however, only approximately 50% of patients respond, and those who do not respond or who relapse carry a poor prognosis with a median survival of 4–6 months.1 Rigosertib is a novel agent that inhibits cellular signalling by targeting the Ras-binding domain. It has demonstrated clinical activity as a single agent in patients with MDS and acute myeloid leukaemia (AML). We designed a Phase I/II study of standard-dose azacitidine (75 mg/m2 injected subcutaneously, or intravenously for 7 days) with oral rigosertib in escalating dose cohorts, based on in vitro data that the two drugs are synergistic in a sequence dependent manner at doses that can be administered in the clinical setting.
Participants could receive prior hypomethylating agents (HMA) (azacitidine or decitabine) but no prior rigosertib. The Phase I component included patients with MDS and AML, both de novo and those failing primary therapy. Patients with AML ≥30 blasts were excluded in the Phase II portion of the study. Response was assessed by International Working Group (IWG) criteria (MDS 2006 and modified AML 2003).2,3 We enrolled 40 MDS patients, of whom 33 were evaluable for response. Their median age was 66 years and 73% were male. Forty-three percent of patients had received prior HMA therapy. Overall response was 76% (complete remission [CR]: 24%; marrow CR with concurrent haematologic improvement [HI]: 30%; marrow CR alone: 18%; HI alone: 3%; stable disease: 24%). There was an 85% response rate in HMA-naïve patients and a 62% response rate in HMA failures. Median time to initial response was two cycles and the median time to best response was three cycles. Responses were fairly evenly distributed among Revised International Prognostic Scoring System (IPSS-R) subgroups. The median overall duration of response was 10.4 months, with a range of 8.1 months for HMA naïve patients and 11.0 months for prior HMA-treated patients.
An additional 10 AML patients were treated during the Phase I portion of the study who mostly had relapsed/refractory/secondary disease. Their median age was 66 years. Eight patients were evaluable for response; 37.5% of patients demonstrated a response, with two achieving morphologic CR and one achieving a morphologic leukaemia-free state.
Adverse events primarily included gastrointestinal toxicity (constipation, diarrhoea, nausea), urinary toxicity (dysuria, haematuria), and fatigue. The adverse events were not significantly different from azacitidine alone.
The study demonstrated that the combination of standard-dose parenteral azacitidine and oral rigosertib was safe and well-tolerated in patients with MDS and AML, with a side effect profile similar to single-agent azacitidine. A Phase II dose expansion is underway to further optimise the dose and schedule of rigosertib. Ultimately, a Phase III randomised study is planned to compare the combination of azacitidine and oral rigosertib to single-agent azacitidine in the HMA naïve MDS population with a primary endpoint of CR plus partial response, given the promising results thus far.