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

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Phase I Trial of the Raf Kinase and Receptor Tyrosine Kinase Inhibitor Sorafenib (BAY 43-9006, Nexavar) in Children and Young Adults With Neurofibromatosis Type 1 and Inoperable

Brief 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

Detailed Summary:

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 a
    Sponsor: National Cancer Institute (NCI)

    Current Primary Outcome: Maximum tolerated dose, chronic toxicity, pharmacokinetics and pharmacodynamics.

    Original Primary Outcome:

    • Maximum-tolerated dose and tolerability of sorafenib tosylate
    • Toxicity according to NCI CTCAE v3.0
    • Bone toxicity as assessed by volumetric MRI analysis, height and growth measurement, dual-energy x-ray absorptiometry, and laboratory measurements for evaluation of bone turnover and metabolism


    Current Secondary Outcome: 3D MRI of plexiform neurofibromas, pharmacodynamics, cognitive function.

    Original Secondary Outcome:

    • PN growth rate as assessed by automated volumetric MRI analysis
    • Adherence to chronic daily dosing with sorafenib as assessed by pill counts, adherence diaries and questionnaire forms


    Information By: National Institutes of Health Clinical Center (CC)

    Dates:
    Date Received: July 31, 2008
    Date Started: July 8, 2008
    Date Completion:
    Last Updated: May 12, 2017
    Last Verified: May 4, 2012