San Diego, CA—A phase 2 expansion-cohort clinical trial has shown encouraging results with the combination of oral rigosertib, a novel styryl benzyl sulfone, and azacitidine (Vidaza) in patients with heavily pretreated myelodysplastic syndromes (MDS) compared with azacitidine monotherapy, according to data presented at ASH 2018.
The combination of rigosertib and azacitidine demonstrated positive outcomes in patients with MDS who had not received a hypomethylating agent (HMA) or had disease refractory to HMA. The combination regimen was well-tolerated and was given in continuing cycles for >2 years, even in those who did not respond to HMA therapy.
“In HMA-naïve patients, oral rigosertib at doses of 840 mg or more per day, administered with azacitidine, was associated with an overall response rate of 90% and, importantly, a complete response rate of 34%,” said Shyamala C. Navada, MD, Assistant Professor, Medicine, Hematology, and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY.
“Based on the safety and efficacy profile of the combination in MDS, a pivotal phase 2 trial is planned in a HMA-naïve population,” Dr Navada added.
In patients with higher-risk MDS, azacitidine is currently the standard first-line therapy, with an overall response rate (ORR) up to 50% and a complete response rate up to 24%. Although different agents have been tested in combination with HMAs, none has demonstrated superiority compared with azacitidine monotherapy. A major reason for the lack of efficacy is the toxicity levels of the drug combinations, said Dr Navada. She noted that the disease ultimately relapses in all patients or does not respond to HMA therapy. Patients have a poor prognosis after a lack of response to HMAs, with a median overall survival of only 4 to 6 months.
“Novel, better tolerated combination strategies for patients with MDS are required to improve clinical outcomes,” Dr Navada emphasized.
In a phase 1 clinical trial of patients with lower-risk MDS, Dr Navada and colleagues studied oral rigosertib as a single agent at various doses, including 560 mg twice daily for 14 to 21 days in 28-day cycles, which yielded a transfusion independence rate of 44%.
Based on these results, the study was expanded to the ongoing expansion cohort clinical trial, using rigosertib 1120 mg daily plus standard-dose azacitidine. In the phase 2 expansion cohort, 45 patients with high-risk MDS were randomized to oral rigosertib 560 mg twice daily plus azacitidine, or to 840 mg in the morning and 280 mg in the afternoon, plus azacitidine. Both cohorts included patients with HMA-naïve and HMA-refractory MDS.
Results Point to Efficacy and Tolerability
Among the HMA-naïve patients who received rigosertib 1120 mg daily, 13 patients were evaluated for a response. The ORR was 92%, including 31% complete response. The responses were durable, with a median duration of response of 13.5 months, and treatment is ongoing.
The median time to initial response was 1 cycle, which was faster than historical data with azacitidine monotherapy.
Among those with HMA-refractory MDS who received 1120 mg daily of rigosertib, 16 were evaluated for response, showing a 50% ORR, including 12% complete or partial responses.
“Median duration of response was 9.2 months, which is important in a population with HMA failure where approximately half of patients had received previous chemotherapy in addition to HMAs,” Dr Navada said.
For patients with HMA-naïve MDS who received rigosertib ≥840 mg/day, a total of 29 underwent evaluation for a response. The ORR was 90%, and the complete response was 34%. The median duration of response was 12.2 months, with patients still receiving treatment for more than 2 years. These patients tolerated repetitive 28-day cycles of treatment.
Among patients with HMA-refractory MDS who received rigosertib ≥840 mg daily, 26 were evaluated for a response. The ORR was 54%, including 8% complete or partial responses, and a median duration of response of approximately 11 months.
“This is an important observation in this heavily pretreated group, where about one-third of patients received previous chemotherapy in addition to HMAs, and these patients also tolerated repetitive 28-day cycles,” said Dr Navada.
Complete responses persisted for 2 to 24 months. The median duration of response was 12.2 months in patients with HMA-naïve MDS and 10.8 months in those with HMA-refractory disease. A pivotal phase 3 clinical trial is planned based on the encouraging results from this trial.