title: Phase I clinical trial of oral rigosertib in patients with myelodysplastic syndromes.
abstract: The multi-kinase inhibitor rigosertib (ON 01910.Na) induces mitotic arrest and apoptosis in myeloblasts, while sparing normal cells. The purpose of this study was to determine the pharmacokinetic profile, maximum-tolerated dose (MTD), safety, and clinical activity of an oral formulation of rigosertib in patients with myelodysplastic syndromes (MDS). For pharmacokinetic studies, patients received rigosertib in single escalating weekly doses. To determine the MTD, patient cohorts received escalating doses of rigosertib twice daily for 14 d of a 21-d cycle. Overall, 37 patients were treated. Rigosertib exposure increased with escalating oral doses. Mean absolute oral bioavailability ranged from 13·9% (fed) to 34·8% (fasting) in 12 patients treated at the 560 mg b.i.d. dose level. Dose-limiting toxicity (grade 3 dysuria and shortness of breath) occurred at the 700 mg b.i.d. dose. Five patients experienced grade 3 non-haematological toxicity, including symptoms of urothelial inflammation, hypotension and syncope, fatigue and abdominal pain. Encouraging signs of clinical activity included two bone marrow complete remissions in refractory anaemia with excess blasts type 1 patients previously treated with azacitidine. In addition, four patients each achieved transfusion independence and haematological improvements. In conclusion, oral rigosertib is bioavailable and well tolerated, and has clinical activity in patients with MDS.
authors.affiliation: Department of Hematological Malignancies, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. rami.komrokji@moffitt.org
authors.forename: Rami S
authors.initials: RS
authors.lastname: Komrokji
authors.forename: Azra
authors.initials: A
authors.lastname: Raza
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lancet
authors.forename: Chen
authors.initials: C
authors.lastname: Ren
authors.forename: David
authors.initials: D
authors.lastname: Taft
authors.forename: Manoj
authors.initials: M
authors.lastname: Maniar
authors.forename: Francois
authors.initials: F
authors.lastname: Wilhelm
authors.forename: Alan F
authors.initials: AF
authors.lastname: List
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D001682:Biological Availability; D002214:Capsules; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004417:Dyspnea / Q000139:chemically induced; D005260:Female; D018565:Food-Drug Interactions; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D005998:Glycine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012074:Remission Induction; D013450:Sulfones / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D014570:Urologic Diseases / Q000139:chemically induced
chemical_list: D002214:Capsules; D047428:Protein Kinase Inhibitors; D013450:Sulfones; C507134:ON 01910; D005998:Glycine
keywords: myelodysplastic syndromes; phosphoinositide-3-kinase; polo-like kinase; rigosertib