On February 19, 2014 Onconova announced that the Phase 3 ONTIME trial of intravenous (IV) rigosertib in patients with higher risk myelodysplastic syndromes (MDS) who had progressed on, failed or relapsed after prior therapy with hypomethylating agents (HMAs) did not meet the primary endpoint of overall survival compared to best supportive care (BSC) (Press release Onconova, FEB 19, 2014, View Source [SID:1234500101]). The ONTIME trial enrolled 299 patients including 199 patients in the IV rigosertib plus BSC arm. Median overall survival in the IV rigosertib plus BSC arm was 8.2 months compared to 5.8 months in BSC only arm. Treatment with IV rigosertib plus BSC did not demonstrate a statistically significant improvement in median overall survival when compared to BSC only (Hazard Ratio=0.86; p-value=0.27).
However, a post-hoc analysis demonstrated a statistically significant increase in median overall survival in the subset of patients who had progressed on or failed previous treatment with HMAs (i.e., had not responded to HMAs), thus demonstrating potential activity of rigosertib in these MDS patients. In this subset of patients (184 of 299 enrolled patients), the median overall survival was 8.5 months in the IV rigosertib plus BSC arm compared to 4.7 months in BSC only arm (Hazard Ratio=0.67; p-value=0.022). Among this patient population, 127 patients were in the treatment arm, and 57 patients were in the BSC arm. The other subset which was comprised of patients who had relapsed after responding to previous treatment with HMAs (115 of 299 patients enrolled), did not show a statistically significant survival benefit. Additional analysis is underway to identify potential survival benefit in other subsets of patients.
Preliminary safety analysis indicates that rigosertib was generally well tolerated in the study population. Severe adverse events were uncommon, with a similar profile of serious adverse events in both study arms. Grade 3/4 treatment-related hematologic and non-hematologic adverse events were reported in less than 7% and 3% of patients, respectively. Incidence of all grades of treatment-related nausea, diarrhea, fatigue and constipation were 22%, 17%, 17%, and 15%, respectively. All other treatment-related adverse events were reported in less than 10% of patients. Additional details, including secondary endpoints, will be presented at the 2014 ASCO (Free ASCO Whitepaper) Annual Meeting.
Onconova is working closely with its partners, Baxter and SymBio, as they evaluate the results of this study. It plans to engage with the U.S. Food and Drug Administration (FDA) and European regulatory agencies with the goal of determining the next steps in advancing development of rigosertib for this underserved patient population. It remains committed to advancing rigosertib to address important medical needs in MDS and solid tumors. Ongoing efforts include trials of oral rigosertib in transfusion-dependent lower risk MDS patients, where, after consultation with regulatory agencies, it is planning to initiate a Phase 3 trial as soon as possible.