R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas
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.
Neurofibromatosis Type I
|Study Design:||Allocation: Randomized
Intervention Model: Crossover Assignment
Primary Purpose: Prevention
|Official Title:||A Phase II Randomized, Cross-Over, Double-Blinded, Placebo-Controlled Trial of the Farnesyltransferase Inhibitor R115777 in Pediatric Patients With Neurofibromatosis Type I and Progressive Plexiform Neurofibromas|
- Median Time to Progression [ Time Frame: 8 years ] [ Designated as safety issue: No ]Median time to progression is defined as a greater than or equal to 20% increase increase in the sum of the volume of all index lesions based on volumetric analysis utilizing magnetic resonance imaging (MRI).Start of phase A or phase B to time of progression.
- Number of Participants With Adverse Events [ Time Frame: 8 years ] [ Designated as safety issue: Yes ]Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
|Study Start Date:||July 2001|
|Study Completion Date:||November 2010|
|Primary Completion Date:||March 2010 (Final data collection date for primary outcome measure)|
Experimental: Tipifarnib (R11577)-Arm I
Patients receive oral R115777 (Tipifarnib) first followed by placebo. 200 mg/m^2/dose BSA every 12 hours by mouth (po)on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Given orally, 200 mg/m^2/dose BSA every 12 hours by mouth (po) daily x 21 days, Course is every 28 days
Other Name: R115777
Placebo Comparator: Placebo-Arm II
Patients receive oral placebo first followed by R115777 (Tipifarnib). 200 mg/m^2/dose BSA every 12 hours by mouth (po)every 12 hours on days 1-21. Courses repeat as in arm I.
Patients receive oral placebo every 12 hours on days 1-21. Courses repeat as in arm I.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00021541
|United States, Alabama|
|University of Alabama at Birmingham (M1149)|
|Birmingham, Alabama, United States, 35233|
|United States, California|
|Children's Hospital Los Angeles, CA (M1118)|
|Los Angeles, California, United States, 90027|
|United States, Illinois|
|Children's Memorial Hospital, Chicago, IL (M1484)|
|Chicago, Illinois, United States, 60614|
|United States, Maryland|
|Johns Hopkins Oncology Center (M1011)|
|Baltimore, Maryland, United States, 21231|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|United States, Massachusetts|
|The Children's Hospital, Dana-Farber Cancer Institute, Boston, MA (M1034)|
|Boston, Massachusetts, United States, 02115|
|United States, Missouri|
|St. Louis Children's Hospital, St. Louis, MO (M1123)|
|St. Louis, Missouri, United States, 63110|
|United States, New York|
|SUNY Upstate Medical University, NY (M1303)|
|Syracuse, New York, United States, 13210|
|United States, Ohio|
|Cincinnati Children's Hospital (FWA 00002988)|
|Cincinnati, Ohio, United States, 45229|
|United States, Pennsylvania|
|Childrens Hospital of Philadelphia, PA (M1257)|
|Philadelphia, Pennsylvania, United States, 19104|
|United States, Texas|
|Texas Children's Hospital, Houston, TX (M1060)|
|Houston, Texas, United States, 77030|
|Klinikum Nord, Hamburg, Germany (FWA 00003228)|
|Hamburg, Germany, D-22419|
|Principal Investigator:||Brigitte Widemann, M.D.||National Insitutes of Health, National Cancer Institute|