On March 26, 2018 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a Phase 3 clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, reported that new clinical safety data from the expansion phase of a Phase 2 clinical trial at the Bone Marrow Failure Disease Scientific Symposium, held in Rockville, Maryland, on March 22-23, 2018 (Press release, Onconova, MAR 26, 2018, View Source [SID1234524993]).
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Oral rigosertib has been developed as a single agent and in combination with azacitidine. Previous studies have demonstrated that Low-Risk (LR) MDS patients with intermittent oral rigosertib treatment at a dose of 560 mg BID show a transfusion independence rate (TI), as defined by the IWG 2006 criteria, of 44% (Raza, et al, Blood 2017 130:1689). Oral rigosertib in combination with AZA is being studied in patients with Higher-risk (HR) MDS. Initial results of the Phase 2 study with oral rigosertib (840 mg /day 3 out of 4 weeks) in combination with azacitidine in patients with MDS demonstrated an overall response rate of 76%; 62% in patients following hypomethylating agent (HMA) failure; and 85% in HMA naïve patients (Navada et al, EHA (Free EHA Whitepaper), 2017). In both single agent and combination studies, oral rigosertib has been associated with hematuria in a subset of patients which has been shown to be dose and administration scheme dependent (Garcia-Manero G, Blood 2016 128:2011). The results reported here are from a dose exploration study in HR MDS patients with an increased oral rigosertib dose (1120 mg/day 3 out of 4 weeks) and focus on the impact of risk-mitigation strategies in minimizing the incidence of urinary adverse events (UAEs); including hematuria. The mitigation strategies included prescribing the second dose of rigosertib earlier in the day and encouraging bladder emptying at bedtime.
The reported incidence of hematuria of any grade with single agent azacitidine is 6.3%, including 2.3% grade 3 and 4 events (per product insert). In the combination trial of oral rigosertib (total dose of 840 mg/day 3 out of 4 weeks) and azacitidine, the incidence of hematuria was 48%, with grade 3 or grade4 AEs of 12%. In the new study, in 37 patients studied with oral rigosertib (total dose of 1120 mg/day 3 out of 4 weeks) and azacitidine employing prophylactic risk-mitigating strategies to minimize hematuria, a significantly lower incidence of grade 1 & 2 hematuria (11%), and no grade 3 or 4 hematuria have been seen to date.
Guillermo Garcia-Manero, M.D, Professor and Chief of the MDS Section at the MD Anderson Cancer Center, who presented the new results, commented, "Choices are very limited for higher risk MDS, with two HMAs as the only drugs approved by the Health Authorities for these patients. There is an urgent need to develop novel approaches, including combination therapies that can improve the outcomes in patients who require an HMA. The previously presented studies of the combination regimen of oral rigosertib with azacitidine have demonstrated impressive evidence of efficacy in HMA naïve and HMA refractory patients with higher-risk MDS. Since the success of a combination therapy is greatly influenced by the safety and tolerability of the regimen, the new results of improved tolerability are of great importance for the proposed pivotal study of this combination. The ability to ensure longer duration of treatment without interruption or dose reduction due to an acceptable safety profile can ensure optimal benefit for patients. We look forward to participating in the planned Phase 3 study of this novel approach, which combines two agents with distinct mechanisms of action for the potential benefit of frontline MDS patients."
Dose optimization and risk mitigation strategies undertaken specifically to minimize UAEs associated with oral rigosertib in combination with azacitidine have resulted, to date, in a decrease in frequency of hematuria from 48% to 11% and elimination of any serious grade 3 events. Minimization of AEs permits patients to continue on treatment to optimize the potential benefit. Reduction in incidence of hematuria also enables the continued study of oral rigosertib in LR-MDS, based on the promising TI Rate previously reported.
A copy of the poster is available by visiting the Scientific Presentations section of Onconova’s website.