title: Phase I trial and pharmacokinetic study of sorafenib in children with neurofibromatosis type I and plexiform neurofibromas.
abstract: BACKGROUND
  Sorafenib targets multiple pathways thought to be crucial in growth of plexiform neurofibroma (PN) in children with neurofibromatosis type 1 (NF1). Sorafenib has been tolerated with manageable toxicities in adults and children with refractory cancer. We conducted a separate study in this population. Monitoring long-term toxicities such as effects on growth and obtaining additional pharmacokinetic data were of importance due to the young age and long duration of therapy seen in previous phase I trials in children with NF1.
  
  
  METHODS
  Children ≥3 and ≤18-year-old with NF1 and inoperable PN were eligible. Sorafenib was administered orally twice daily for consecutive 28-day cycles. Maximum tolerated dose (MTD) was determined from toxicities observed during the first three cycles.
  
  
  RESULTS
  Nine children enrolled, median age 8 (6-12) years. At the starting 115 mg/m(2) /dose (n = 5), two experienced dose-limiting grade 3 pain in their PN. At the de-escalated 80 mg/m(2) /dose (n = 4), approximately 40% of the pediatric solid tumor MTD, two had dose-limiting toxicity (grade 3 rash and grade 4 mood alteration), exceeding the MTD. At 80 mg/m(2) /dose, the median AUC(0-12 hours) at steady-state was 39.5 µg hours/ml. Toxicities appeared to correspond with decreases in quality of life (QOL). No tumor shrinkage was observed.
  
  
  CONCLUSIONS
  Children with NF1 and PN did not tolerate sorafenib at doses substantially lower than the MTD in children and adults with malignant solid tumors. Future trials with targeted agents for children with NF1 may require a more conservative starting dose and separate definitions of dose limiting toxicities (DLT) than children with cancer.
authors.affiliation: Pediatric Oncology Branch, NCI, CCR, Bethesda, Maryland, USA. aekim@childrensnational.org
authors.forename: AeRang
authors.initials: A
authors.lastname: Kim
authors.forename: Eva
authors.initials: E
authors.lastname: Dombi
authors.forename: Kathleen
authors.initials: K
authors.lastname: Tepas
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fox
authors.forename: Staci
authors.initials: S
authors.lastname: Martin
authors.forename: Pamela
authors.initials: P
authors.lastname: Wolters
authors.forename: Frank M
authors.initials: FM
authors.lastname: Balis
authors.forename: Nalini
authors.initials: N
authors.lastname: Jayaprakash
authors.forename: Baris
authors.initials: B
authors.lastname: Turkbey
authors.forename: Naira
authors.initials: N
authors.lastname: Muradyan
authors.forename: Peter L
authors.initials: PL
authors.lastname: Choyke
authors.forename: Alyssa
authors.initials: A
authors.lastname: Reddy
authors.forename: Bruce
authors.initials: B
authors.lastname: Korf
authors.forename: Brigitte C
authors.initials: BC
authors.lastname: Widemann
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D018318:Neurofibroma, Plexiform / Q000188:drug therapy* / Q000209:etiology; D009456:Neurofibromatosis 1 / Q000150:complications / Q000188:drug therapy*; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib