Sorafenib to Treat Children and Young Adults With Neurofibromatosis Type 1 and Inoperable Plexiform Neurofibromas
Condition: Neurofibromatosis Type I; Plexiform Neurofibroma
MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurofibroma, Plexiform
Study type: Interventional
Phase: Phase 1

Summary: 
      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.

      ...
    

Detailed description: 
      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.
    

Intervention name(s): Nexavar (BAY 43-9006) (Sorafenib); Toxicity, Pharmacokinetics; Pharmacodynamics; Radiographic Evaluation; QOL assessment, Neuropsychological; Bony Toxicity
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention MeSH terms: Sorafenib
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Neuroblastosis Type I; Plexiform Neurofibromas; Angiogenesis Inhibitor; Kinase Inhibitor; Neurofibromatosis Type 1; NF1; Plexiform Neurofibroma