Phase I trial and pharmacokinetic study of sorafenib in children with neurofibromatosis type I and plexiform neurofibromas

Aerang Kim, Eva Dombi, Kathleen Tepas, Elizabeth Fox, Staci Martin, Pamela Wolters, Frank M. Balis, Nalini Jayaprakash, Baris Turkbey, Naira Muradyan, Peter L. Choyke, Alyssa Reddy, Bruce Korf, Brigitte C. Widemann

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


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. Procedure: 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 115mg/m2/dose (n=5), two experienced dose-limiting grade 3 pain in their PN. At the de-escalated 80mg/m2/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 80mg/m2/dose, the median AUC0-12hours at steady-state was 39.5μghours/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.

Original languageEnglish (US)
Pages (from-to)396-401
Number of pages6
JournalPediatric Blood and Cancer
Issue number3
StatePublished - Mar 2013
Externally publishedYes


  • Neurofibromatosis type I
  • Phase I
  • Plexiform neurofibromas
  • Sorafenib

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology


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