title: A randomized phase I clinical and biologic study of two schedules of sorafenib in patients with myelodysplastic syndrome or acute myeloid leukemia: a NCIC (National Cancer Institute of Canada) Clinical Trials Group Study.
abstract: Sorafenib is a small molecule inhibitor of RAF kinase, VEGFR-2, c-KIT, and FLT3. In this randomized phase I study, eligible patients had relapsed/refractory acute myeloid leukemia (AML), and one prior induction regimen, or were age >65 with untreated myelodysplastic syndrome (MDS) or secondary AML. Sorafenib was given orally for 28 days (cont) or 14 days (int) every 4 weeks at three dose levels (100, 200, and 400 mg BID); 300 mg cont was also tested. Forty-two patients were enrolled (median age 71 [37-82]; prior chemotherapy: 22). Dose-limiting toxicity (DLT) was: 100 mg BID: 0/7 patients; 200 mg BID: 2/12 patients; 400 mg BID: 1/17 patients. Sorafenib 400 mg cont was not tolerated in this population: 6/8 received <14 days of treatment due to toxicity; no DLT was seen with 300 mg cont. One CR was seen in a patient with AML with FLT3-ITD. Flow cytometry studies suggest that sorafenib inhibits ERK phosphorylation via c-KIT. The recommended phase II dose in AML is 300 mg BID continuously, and testing in combination and in FLT3-ITD AML is warranted.
authors.affiliation: National Cancer Institute of Canada Clinical Trials Group. michael.crump@uhn.on.ca
authors.forename: Michael
authors.initials: M
authors.lastname: Crump
authors.forename: David
authors.initials: D
authors.lastname: Hedley
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kamel-Reid
authors.forename: Brian
authors.initials: B
authors.lastname: Leber
authors.forename: Richard
authors.initials: R
authors.lastname: Wells
authors.forename: Joseph
authors.initials: J
authors.lastname: Brandwein
authors.forename: Rena
authors.initials: R
authors.lastname: Buckstein
authors.forename: Janine
authors.initials: J
authors.lastname: Kassis
authors.forename: Mark
authors.initials: M
authors.lastname: Minden
authors.forename: John
authors.initials: J
authors.lastname: Matthews
authors.forename: Sue
authors.initials: S
authors.lastname: Robinson
authors.forename: Robert
authors.initials: R
authors.lastname: Turner
authors.forename: Lynn
authors.initials: L
authors.lastname: McIntosh
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Eisenhauer
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
mesh_terms: D015746:Abdominal Pain / Q000139:chemically induced; D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D001557:Benzenesulfonates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009325:Nausea / Q000139:chemically induced; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D048049:Extracellular Signal-Regulated MAP Kinases