title: Phase I pharmacokinetic and pharmacodynamic study of pazopanib in children with soft tissue sarcoma and other refractory solid tumors: a children's oncology group phase I consortium report.
abstract: OBJECTIVE
  Pazopanib, an oral multikinase angiogenesis inhibitor, prolongs progression-free survival in adults with soft tissue sarcoma (STS). A phase I pharmacokinetic and pharmacodynamic study of two formulations of pazopanib was performed in children with STS or other refractory solid tumors.
  
  
  METHODS
  Pazopanib (tablet formulation) was administered once daily in 28-day cycles at four dose levels (275 to 600 mg/m(2)) using the rolling-six design. Dose determination for a powder suspension was initiated at 50% of the maximum-tolerated dose (MTD) for the intact tablet. Ten patients with STS underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scanning at baseline and 15 ± 2 days after initiation of pazopanib at the tablet MTD.
  
  
  RESULTS
  Fifty-three patients were enrolled; 51 were eligible (26 males; median age, 12.9 years; range, 3.8 to 23.9 years). Hematologic and nonhematologic toxicities were generally mild, with dose-limiting lipase, amylase, and ALT elevation, proteinuria, and hypertension. One patient with occult brain metastasis had grade 4 intracranial hemorrhage. The MTD was 450 mg/m(2) for tablet and 160 mg/m(2) for suspension. Steady-state trough concentrations were reached by day 15 and did not seem to be dose dependent. One patient each with hepatoblastoma or desmoplastic small round cell tumor achieved a partial response; eight patients had stable disease for ≥ six cycles, seven of whom had sarcoma. All patients with evaluable DCE-MRI (n = 8) experienced decreases in tumor blood volume and permeability (P < .01). Placental growth factor increased, whereas endoglin and soluble vascular endothelial growth factor receptor-2 decreased (P < .01; n = 41).
  
  
  CONCLUSIONS
  Pazopanib is well tolerated in children, with evidence of antiangiogenic effect and potential clinical benefit in pediatric sarcoma.
authors.affiliation: Columbia University Medical Center, New York, NY 10032, USA. Jg589@columbia.edu
authors.forename: Julia L
authors.initials: JL
authors.lastname: Glade Bender
authors.forename: Alice
authors.initials: A
authors.lastname: Lee
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Sylvain
authors.initials: S
authors.lastname: Baruchel
authors.forename: Timothy
authors.initials: T
authors.lastname: Roberts
authors.forename: Stephan D
authors.initials: SD
authors.lastname: Voss
authors.forename: Bing
authors.initials: B
authors.lastname: Wu
authors.forename: Charlotte H
authors.initials: CH
authors.lastname: Ahern
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Ingle
authors.forename: Pamela
authors.initials: P
authors.lastname: Harris
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Weigel
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
mesh_terms: D000293:Adolescent; D000328:Adult; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007191:Indazoles; D008297:Male; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D012509:Sarcoma / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib