title: Phase I and pharmacokinetic study of sunitinib in pediatric patients with refractory solid tumors: a children's oncology group study.
abstract: OBJECTIVE
  Sunitinib is an oral multitargeted receptor tyrosine kinase inhibitor. The purpose of this study was to determine the recommended phase 2 dose, pharmacokinetics, pharmacodynamic effects, and preliminary antitumor activity of sunitinib in a pediatric population.
  
  
  METHODS
  Patients who were 2 to 21 years of age with refractory solid tumors were eligible if they had measurable or evaluable disease and met baseline organ function requirements. Patients received sunitinib once daily for 28 days followed by a 14-day break between each cycle. Dose levels of 15 and 20 mg/m(2)/d were evaluated, with dose escalation based on a 3 + 3 design. Sunitinib pharmacokinetics and biomarkers of angiogenesis were also evaluated during the first cycle.
  
  
  RESULTS
  Twenty-three patients were treated (median age 13.9 years; range, 3.9-20.6 years). The most common toxicities were neutropenia, thrombocytopenia, elevated liver transaminases, gastrointestinal symptoms, and fatigue. Two patients developed dose-limiting reductions in cardiac ejection fraction prompting a protocol amendment to exclude patients with previous exposure to anthracyclines or cardiac radiation. In patients without these cardiac risk factors, the maximum tolerated dose (MTD) was 15 mg/m(2)/d. Steady-state plasma concentrations were reached by day 7. No objective responses were observed. Four patients with sarcoma and glioma had stable disease for 2 to 9 cycles.
  
  
  CONCLUSIONS
  Cardiac toxicity precluded determination of a recommended dose for pediatric patients with previous anthracycline or cardiac radiation exposure. The MTD of sunitinib for patients without risk factors for cardiac toxicity is 15 mg/m(2)/d for 28 days followed by a 14-day break.
authors.affiliation: Department of Pediatrics, University of California, San Francisco School of Medicine, San Francisco, CA 94143-0106, USA. duboiss@peds.ucsf.edu
authors.forename: Steven G
authors.initials: SG
authors.lastname: Dubois
authors.forename: Suzanne
authors.initials: S
authors.lastname: Shusterman
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Ingle
authors.forename: Charlotte H
authors.initials: CH
authors.lastname: Ahern
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Bing
authors.initials: B
authors.lastname: Wu
authors.forename: Sylvain
authors.initials: S
authors.lastname: Baruchel
authors.forename: Julia
authors.initials: J
authors.lastname: Glade-Bender
authors.forename: Percy
authors.initials: P
authors.lastname: Ivy
authors.forename: Holcombe E
authors.initials: HE
authors.lastname: Grier
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006321:Heart / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D011758:Pyrroles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib