Phase I study of the safety, pharmacokinetics and antitumor activity of famitinib

Cancer Chemother Pharmacol. 2013 Nov;72(5):1043-53. doi: 10.1007/s00280-013-2282-y. Epub 2013 Sep 17.

Abstract

Purpose: To evaluate the safety, tolerability, pharmacokinetics and antitumor activities of famitinib (famitinib L-malate), a novel oral multitargeting tyrosine kinase inhibitor that acts against vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor, stem cell factor receptor (c-kit), FMS-like tyrosine kinase-3 receptor and protooncogene tyrosine kinase receptor in patients with advanced solid cancer.

Methods: Patients received once daily oral famitinib. Doses were increased from 4 to 8, 13, 20, 27, 24, 25 and eventually 30 mg. Each cycle was defined as 28 days. The pharmacokinetic profile and various biomarkers were evaluated during the first cycle. Antitumor efficacy was evaluated every 8 weeks.

Results: Fifty-four patients were evaluable for safety and efficacy. Dose-limiting toxicities were observed in 2 of 3 patients at 30 mg. The dose-limiting toxicities observed in the first cycle of famitinib treatment included hypertension, hand-foot skin reaction and diarrhea. Grade 3 hypertriglyceridemia/hypercholesterolemia and proteinuria were notable side effects in the subsequent treatment cycles. Other common side effects included bone marrow suppression, oral mucositis, fatigue, pain, elevated transaminase or bilirubin, peripheral sensory disturbance and hypothyroidism, most of which were mild to moderate in severity. Pharmacokinetic studies revealed no significant accumulation of famitinib or its major metabolite, M3. The half-lives of famitinib and M3 were approximately 28.7-33.8 and 41.3-47.7 h, respectively. Food demonstrated a minimal effect on the pharmacokinetics of famitinib. Eight partial responses were determined, including 6 cases of renal cell carcinoma, 1 case of gastrointestinal stromal tumor (GIST) and 1 case of alveolar soft part sarcoma. Fourteen patients demonstrated stable disease with various degrees of tumor shrinkage.

Conclusions: Famitinib is generally well tolerated. Famitinib demonstrates a wide spectrum of antitumor activities, which warrants further study in renal cell carcinoma, GIST, hepatocellular carcinoma and soft tissue sarcoma. The recommended dose for future phase II clinical trials is 25 mg.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Angiogenesis Inhibitors / administration & dosage
  • Angiogenesis Inhibitors / adverse effects
  • Angiogenesis Inhibitors / pharmacokinetics
  • Angiogenesis Inhibitors / therapeutic use*
  • Biotransformation
  • Carcinoma, Renal Cell / blood
  • Carcinoma, Renal Cell / drug therapy
  • China / epidemiology
  • Cohort Studies
  • Dose-Response Relationship, Drug
  • Female
  • Half-Life
  • Humans
  • Hypertension / chemically induced
  • Hypertension / epidemiology
  • Incidence
  • Indoles / administration & dosage
  • Indoles / adverse effects
  • Indoles / pharmacokinetics
  • Indoles / therapeutic use*
  • Kidney Neoplasms / blood
  • Kidney Neoplasms / drug therapy
  • Male
  • Middle Aged
  • Neoplasms / blood
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Postprandial Period
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrroles / administration & dosage
  • Pyrroles / adverse effects
  • Pyrroles / pharmacokinetics
  • Pyrroles / therapeutic use*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Sarcoma / blood
  • Sarcoma / drug therapy
  • Young Adult

Substances

  • Angiogenesis Inhibitors
  • Indoles
  • Protein Kinase Inhibitors
  • Pyrroles
  • famitinib
  • Receptor Protein-Tyrosine Kinases