TY - JOUR
T1 - Rigosertib in combination with azacitidine in patients with myelodysplastic syndromes or acute myeloid leukemia
T2 - Results of a phase 1 study
AU - Navada, Shyamala C.
AU - Garcia-Manero, Guillermo
AU - OdchimarReissig, Rosalie
AU - Pemmaraju, Naveen
AU - Alvarado, Yesid
AU - Ohanian, Maro N.
AU - John, Rosmy B.
AU - Demakos, Erin P.
AU - Zbyszewski, Patrick S.
AU - Maniar, Manoj
AU - Woodman, Richard C.
AU - Fruchtman, Steven M.
AU - Silverman, Lewis R.
N1 - Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/7
Y1 - 2020/7
N2 - 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.
AB - 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.
KW - Acute myeloid leukemia
KW - Myelodysplastic syndrome
KW - Ras inhibitor
KW - Rigosertib
UR - http://www.scopus.com/inward/record.url?scp=85084656241&partnerID=8YFLogxK
U2 - 10.1016/j.leukres.2020.106369
DO - 10.1016/j.leukres.2020.106369
M3 - Article
C2 - 32442785
AN - SCOPUS:85084656241
SN - 0145-2126
VL - 94
JO - Leukemia Research
JF - Leukemia Research
M1 - 106369
ER -