Rigosertib in Combination With Azacitidine in Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia: Results of a Phase 1 Study | Aplastic Anemia & MDS International Foundation

Rigosertib in Combination With Azacitidine in Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia: Results of a Phase 1 Study

Journal Title: 
Leukemia Research
Primary Author: 
Shyamala C Navada
Author(s): 
Shyamala C Navada, Guillermo Garcia-Manero, Rosalie OdchimarReissig, Naveen Pemmaraju, Yesid Alvarado, Maro N Ohanian, Rosmy B John, Erin P Demakos, Patrick S Zbyszewski, Manoj Maniar, Richard C Woodman, Steven M Fruchtman, Lewis R Silverman
Original Publication Date: 
Wednesday, July 1, 2020

Phase 1 results from a Phase 1/2 study comprise 18 patients with myelodysplastic syndromes (MDS; n = 9), acute myeloid leukemia (AML; n = 8), and chronic myelomonocytic leukemia (CMML; n = 1) who were either hypomethylating agent naïve (n = 10) or relapsed/refractory following prior hypomethylating agent therapy (n = 8) (NCT01926587). Patients received oral rigosertib, an inhibitor of Ras-effector pathways, in 3 successive cohorts (140 mg twice daily, 280 mg twice daily, or 840 mg/day [560 mg morning/280 mg evening]) for 3 weeks of a 4-week cycle. Patients received parenteral azacitidine (75 mg/m2/day × 7 days) during the second week; the cycle repeated every 4 weeks. The combination was well tolerated for a median of 4 (range 1-41) cycles, with 72% of patients experiencing ≥1 serious adverse events. No dose-limiting toxicities were observed. Thus, no maximum tolerated dose was reached. The most frequently reported adverse events were diarrhea (50%), constipation, fatigue, and nausea (each 44%), and pneumonia and back pain (each 33%). Sequential administration demonstrated an overall response rate of 56% in evaluable patients, with responses observed in 7/9 MDS/CMML patients (78%) and 2/7 AML patients (29%). Further clinical studies are warranted to investigate this doublet therapy in patients with myeloid malignancies.