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

Leuk Lymphoma. 2010 Feb;51(2):252-60. doi: 10.3109/10428190903585286.

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.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • Abdominal Pain / chemically induced
  • Acute Disease
  • Adult
  • Aged
  • Aged, 80 and over
  • Area Under Curve
  • Benzenesulfonates / adverse effects
  • Benzenesulfonates / pharmacokinetics
  • Benzenesulfonates / therapeutic use*
  • Diarrhea / chemically induced
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Humans
  • Leukemia, Myeloid / drug therapy*
  • Leukemia, Myeloid / metabolism
  • Leukemia, Myeloid / pathology
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Myelodysplastic Syndromes / drug therapy*
  • Myelodysplastic Syndromes / metabolism
  • Myelodysplastic Syndromes / pathology
  • Nausea / chemically induced
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / therapeutic use
  • Pyridines / adverse effects
  • Pyridines / pharmacokinetics
  • Pyridines / therapeutic use*
  • Sorafenib
  • Treatment Outcome

Substances

  • Benzenesulfonates
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Pyridines
  • Niacinamide
  • Sorafenib
  • Extracellular Signal-Regulated MAP Kinases