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. 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 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.