R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas
Condition: Neurofibroma, Plexiform; Neurofibromatosis Type I
MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurofibroma, Plexiform
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will examine whether the experimental drug R115777 (Tipifarnib) can shrink or slow
      the growth of plexiform neurofibromas in children and young adults with neurofibromatosis
      type 1 (NF1) and determine what side effects are related to treatment. Plexiform tumors arise
      from nerves; the only effective treatment is surgical removal. Often, however, not all the
      tumors can be removed, because of their number or location.

      Patients with NF1 have a reduced amount of the protein neurofibromin. Neurofibromin is
      thought to help control the activity of another protein, called ras, which regulates cell
      growth. Too little neurofibromin, therefore, may allow for uncontrolled cell growth and tumor
      formation. R115777 interferes with the function of the ras and other proteins. In test tube
      and animal studies, R115777 has blocked the growth of cancer cells. This study will examine
      whether the drug is effective against plexiform tumors.

      Patients with NF1 and progressive plexiform neurofibromas between 3 and 25 years of age may
      be eligible for this study. Patients whose tumors can be successfully removed surgically may
      not participate in this study. Candidates are screened with a medical history and physical
      and eye examinations, blood and urine tests, and magnetic resonance imaging (MRI).
      Photographs are taken of tumors visible on the body surface.

      Study participants are randomly assigned to receive either R115777 or placebo (an inactive
      substance). They take R115777 or placebo tablets every 12 hours for 21 days, followed by a
      7-day rest period. This constitutes one 28-day treatment cycle. Treatment continues for as
      long as the tumors remain stable or shrink and side effects are tolerable. The treatment is
      switched (for example, from placebo to R115777) or stopped if the tumors grow or if side
      effects become unacceptable. Patients (or their parents) keep a record of side effects.

      For the first 3 treatment cycles, patients have a physical examination and blood tests every
      other week. Blood tests are also done before starting treatment, and at one time point after
      at least 14 days of treatment to measure the effect of R115777 on proteins in blood cells. A
      blood sample is obtained before starting treatment and before cycles 4, 7 and 10 and then
      after every 6 cycles to measure the level of a substance called nerve growth factor. The
      analysis of nerve growth factor is used to determine if it can predict which patients might
      be at risk of developing side effects from R115777.
    

Detailed description: 
      R115777 (Tipifarnib) is a farnesyltransferase inhibitor that blocks the post-translational
      isoprenylation of ras and other farnesylated proteins. The ras proteins are integral in cell
      signaling pathways, and farnesylation is essential for the function of both mutant and
      non-mutant ras proteins. Patients with neurofibromatosis type 1 (NF1) have an increased risk
      of developing tumors of the central and peripheral nervous system, and there are no standard
      treatment options, other than surgery, available for these tumors. Neurofibromin, which is
      the product of the NF1 gene, contains a domain with significant homology to ras
      GTPase-activating proteins (GAP). Although NF1 patients lack germline ras mutations, the
      decreased levels of neurofibromin have been shown to be associated with a constitutively
      activated ras-GTP status. Thus, upstream inhibition of ras farnesylation may inhibit growth
      of tumors in NF1 patients. A randomized, cross-over, double-blinded, placebo-controlled
      pediatric phase II trial of oral R115777 will be performed in children and young adults with
      NF1, who have progressive, plexiform neurofibroma(s) to determine the effect of this novel
      anticancer drug on the rate of growth of neurofibromas. The endpoint of the trial is time to
      progression. R115777 will be administered orally at a dose of 200 mg/m(2) twice daily for
      cycles of 21 days followed by a 7 day rest period based on the results of our prior pediatric
      phase I trial.
    

Intervention name(s): tipifarnib; placebo
Intervention type(s): Drug; Other
Intervention description(s): Given orally, 200 mg/m^2/dose BSA every 12 hours by mouth (po) daily x 21 days, Course is every 28 days; Patients receive oral placebo every 12 hours on days 1-21. Courses repeat as in arm I.
Other intervention name(s): R115777
Intervention MeSH terms: Tipifarnib
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Prevention
Keywords: Surrogate Markers; 3-Dimensional Magnetic Resonance Imaging (MRI); Natural History of Neurofibromatosis Type 1 (NF1); Tumor Tissue Bank; Neurofibromatosis; NF1; Neurofibromatosis Type 1; Plexiform Neurofibroma; Neurofibroma