Phase I and pharmacokinetic study of sorafenib, an oral multikinase inhibitor, in Japanese patients with advanced refractory solid tumors

Cancer Sci. 2008 Jul;99(7):1492-8. doi: 10.1111/j.1349-7006.2008.00837.x. Epub 2008 May 12.


Sorafenib is a novel oral multikinase inhibitor that targets Raf serine/threonine and receptor tyrosine kinases, and inhibits tumor cell proliferation and angiogenesis. We have conducted a phase I study of sorafenib to determine the safety, tolerability, pharmacokinetics, and potential efficacy of this agent in 31 Japanese patients with advanced refractory solid tumors. Sorafenib (100-600 mg) was given as a single dose followed by a 7-day wash-out period, and then administrated twice daily (bid). The most frequent drug-related adverse events were rash/desquamation (61%), hand-foot skin reactions (39%), diarrhea (36%), and elevations of serum lipase (36%) and amylase (26%) levels. Dose-limiting toxicities (DLTs) were grade 3 diarrhea at 200 mg bid and grade 3 fatigue at 600 mg bid. Grade 3 and 4 pancreatic enzyme elevations were observed at 200-600 mg bid, but they were not deemed dose-limiting because they were asymptomatic and were not associated with pancreatitis or chronic damage to the pancreas. The AUC and C(max) of sorafenib increased linearly with dose up to 400 mg bid. Partial responses were observed in one of 10 patients with non-small cell lung cancer and one of three patients with renal cell carcinoma. In conclusion, sorafenib 400 mg bid was well tolerated in Japanese patients with advanced refractory solid tumors. The recommended dose for future clinical trials is 400 mg bid.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / therapeutic use*
  • Benzenesulfonates / adverse effects
  • Benzenesulfonates / pharmacokinetics
  • Benzenesulfonates / therapeutic use*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Fluorodeoxyglucose F18
  • Humans
  • Male
  • Middle Aged
  • Neoplasms / drug therapy*
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Phosphorylation
  • Positron-Emission Tomography
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyridines / adverse effects
  • Pyridines / pharmacokinetics
  • Pyridines / therapeutic use*
  • Sorafenib


  • Antineoplastic Agents
  • Benzenesulfonates
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Pyridines
  • Fluorodeoxyglucose F18
  • Niacinamide
  • Sorafenib
  • Extracellular Signal-Regulated MAP Kinases