Rigosertib in combination with azacitidine in patients with myelodysplastic syndromes or acute myeloid leukemia: Results of a phase 1 study

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

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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.

Original languageEnglish
Article number106369
JournalLeukemia Research
Volume94
DOIs
StatePublished - Jul 2020

Keywords

  • Acute myeloid leukemia
  • Myelodysplastic syndrome
  • Ras inhibitor
  • Rigosertib

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