Sorafenib to Treat Children and Young Adults With Neurofibromatosis Type 1 and Inoperable Plexiform Neurofibromas

Background: Patients with neurofibromatosis type 1 are at increased risk of developing tumors called plexiform neurofibromas (PN) that arise from nerves. These tumors are usually non-cancerous, but they can cause serious medical problems. Sorafenib was recently approved to treat patients with kidney cancer and is now being tested in children with cancer. It affects several pathways thought to be important for the development and growth of PN and may therefore shrink these tumors or slow their growth. Objectives: To determine the highest dose of sorafenib that can safely be given to children and young adults with PN. To identify the side effects of sorafenib in these patients. To study how the body handles sorafenib by measuring the amount of drug in the bloodstream over time To determine how the drug affects blood flow and blood cells and proteins. To determine if sorafenib can shrink or slow the growth of PN. To determine the effects of sorafenib on learning, attention, memory, and quality of life. Eligibility: Patients between 3 and 18 years of age with NF1 who have inoperable PN that can cause significant disability. Design: Patients take sorafenib tablets twice a day in 28-day treatment cycles. They may continue treatment until their tumor grows or they develop unacceptable drug side effects. In this dose escalation study, the dosage is increased with every 3 to 6 children who are enrolled until the highest safe dose is determined. In any case, the dose will not exceed that used in children with cancer. Patients are monitored regularly with physical examinations, blood and urine tests, MRI scans and quality-of-life questionnaires. Patients whose bones are still growing have periodic x-rays of the hips and lower legs to monitor for possible changes in the structure of growing bones. Patients have periodic tests of learning and memory before starting treatment and before cycles 4, 12, 18 and 24. Patients have pharmacokinetic studies to examine how the body handles sorafenib. blood samples are drawn before the first dose of sorafenib and then at 30 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, 10 to 12 hours, 24 hours and 30 to 36 hours following the first dose. ...

Background: * Patients with Neurofibromatosis 1 (NF1) have an increased risk of developing tumors of the central and peripheral nervous system, including plexiform neurofibromas (PN), which are benign nerve sheath tumors that are among the most debilitating complications of NF1. Plexiform neurofibromas may be congenital and appear to have the fastest growth rate in young children. There are no standard treatment options for PN other than surgery, which is often difficult due to the extensive growth and invasion of surrounding tissues. * Plexiform neurofibromas are composed of neoplastic Schwann cells that lack NF1 gene expression resulting in upregulation of Ras, which initiates several signaling cascades regulating cell proliferation. In addition, PN over express epidermal and platelet derived growth factor receptor and vascular endothelial growth factors, which may promote angiogenesis. * Sorafenib, a novel orally bioavailable, bi-aryl urea, is a potent inhibitor of raf kinase and a number of receptor tyrosine kinases, which is currently undergoing evaluation in adult cancers, and may mediate anti-tumor effects in PN by several mechanisms. Objectives: * To determine the maximum tolerated dose (MTD) of oral sorafenib administered daily to pediatric patients with NF1 and inoperable PN. * To define the acute and chronic toxicities, pharmacokinetics, and pharmacodynamics of sorafenib. * To evaluate for potential bone toxicities of sorafenib such as growth plate expansion and growth retardation using automated volumetric MRI analysis of growth plates, multiple measures for height and growth, dual-energy x-ray absorptiometry to evaluate bone mineral density, and laboratory measurements for evaluation of bone turnover and metabolism. * To determine the effect of sorafenib on the growth rate of PN, quality of life, and cognitive function while on treatment with sorafenib. Eligibility: \- Pediatric Patients (3-18 years) with NF1 and inoperable measurable PN that have the potential to cause significant morbidity. Design: * Sorafenib will be administered orally BID on a continuous dosing schedule (28 days = 1 treatment cycle). Limited dose escalations will be performed to define the MTD based on tolerability of sorafenib during the first three treatment cycles. * Disease status will be evaluated using volumetric MRI analysis at regular intervals. * The plasma pharmacokinetics and pharmacodynamics of sorafenib will be evaluated. * Cognitive function and quality of life outcomes will also be assessed in a pilot fashion to define measures to be used in subsequent phase II trials.