R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas
- Conditions
- Neurofibromatosis Type INeurofibroma, Plexiform
- Interventions
- Other: placebo
- Registration Number
- NCT00021541
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 62
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Placebo-Arm II placebo 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. Tipifarnib (R11577)-Arm I tipifarnib 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.
- Primary Outcome Measures
Name Time Method Median Time to Progression 8 years 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 8 years Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
- Secondary Outcome Measures
Name Time Method Quality of Life (QOL) Baseline to pre cycle 4 Parents of participants aged 6-18 years completed the Impact of Pediatric Illness (IPI) Scale about their child prior to the start of cycles 1, 4, 7, and 10 and then after every 6 cycles. The IPI Scale assesses QOL in 4 domains: adaptive behavior, emotional functioning, medical/physical status, and cognitive functioning. Responses to the 43 items are made on a 5-point Likert scale (1-5) ranging from "not al all" to "a lot". Higher mean scores indicate better QOL. Parent total scores for participants on placebo were compared with scores from participants receiving tipifarnib on phase A.
Trial Locations
- Locations (12)
The Children's Hospital, Dana-Farber Cancer Institute, Boston, MA (M1034)
🇺🇸Boston, Massachusetts, United States
Children's Memorial Hospital, Chicago, IL (M1484)
🇺🇸Chicago, Illinois, United States
Childrens Hospital of Philadelphia, PA (M1257)
🇺🇸Philadelphia, Pennsylvania, United States
Texas Children's Hospital, Houston, TX (M1060)
🇺🇸Houston, Texas, United States
Cincinnati Children's Hospital (FWA 00002988)
🇺🇸Cincinnati, Ohio, United States
Johns Hopkins Oncology Center (M1011)
🇺🇸Baltimore, Maryland, United States
SUNY Upstate Medical University, NY (M1303)
🇺🇸Syracuse, New York, United States
Klinikum Nord, Hamburg, Germany (FWA 00003228)
🇩🇪Hamburg, Germany
University of Alabama at Birmingham (M1149)
🇺🇸Birmingham, Alabama, United States
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States
Children's Hospital Los Angeles, CA (M1118)
🇺🇸Los Angeles, California, United States
St. Louis Children's Hospital, St. Louis, MO (M1123)
🇺🇸Saint Louis, Missouri, United States