A Phase ll Trial of the Farnesyltransferase Inhibitor R115777 in Pediatric Patients with Neurofibromatosis Type 1

Principal Investigator: WIDEMANN, BRIGITTE C
Institution Receiving Award: NATIONAL INSTITUTES OF HEALTH
Program: NFRP
Proposal Number: NF000027
Award Number: 1LCDN9M1152
Funding Mechanism: Clinical Trial Award
Partnering Awards:
Award Amount: $365,683.00


Neurofibromatosis type 1 (NF1) is an inherited disorder, which occurs in 1 out of every 3,000 people. Patients with NF1 have an increased risk of developing tumors of the nervous system for which there are no effective treatments other than surgery. The underlying cause of NF1 is a defective gene. The function of this gene is to produce a protein called neurofibromin. In patients with NF1, neurofibromin is decreased, and the decrease in neurofibromin is felt to contribute directly to tumor formation. Neurofibromin helps control the activity of another protein called ras. Ras can be thought of as an ¿on/off¿ switch for cell growth. When ras is ¿on,¿ cells divide. When ras is ¿off,¿ the cells do not divide. Neurofibromin helps to keep ras turned ¿off.¿ Decreased levels of neurofibromin therefore may allow for uncontrolled cell division and tumor formation. Drugs that inactivate ras are being studied as a new way to treat cancer. These drugs may also provide a logical means of controlling the tumors in patients with NF1. R115777 is a new experimental drug that interferes with the function of the ras protein and other proteins in cells by blocking a step in the formation of these proteins. R115777 can block the growth of cancer cells and tumor cells derived from patients with NF1 in test tubes and in animals. R115777 has completed evaluation in early clinical trials for adults, and for children with refractory cancers and with NF1 and progressive, plexiform neurofibromas. The Pediatric Oncology Branch will open a trial of R115777 for patients with NF1 and growing plexiform neurofibromas that cannot be completely surgically resected. R115777 will be administered in the form of tablets every 12 hours for cycles of 21 days followed by a 7-day rest period. The main purposes of this study are to (1) determine if R115777 can slow down the growth rate of plexiform neurofibromas in patients with NF1, (2) determine if R115777 can result in shrinkage of progressive plexiform neurofibromas, (3) determine the types of side effects that can be produced by R115777 in children and young adults with NF1, and (4) study the biology of the tumors from patients with NF1. (Patients who decline to have a tumor sample taken will still be allowed to participate in the treatment part of this study). The growth of plexiform neurofibromas is unpredictable and can include periods of rapid growth or long periods of no growth. This behavior can make it difficult to measure the effectiveness of R115777 as a treatment for plexiform neurofibromas. In order to find out if R115777 will be helpful for patients with plexiform neurofibromas, the effects of the drug will be compared to a placebo (a similar tablet that does not contain R115777) in each patient who is treated on the study. Before starting any treatment, it will be randomly determined (by coin flip) whether the patient will initially receive either R115777 or placebo. Patients will be followed closely throughout the study for signs of increase of the neurofibroma by clinical examinations, photography, and magnetic resonance imaging (MRI) scans. A new method to evaluate MRI scans called volumetric analysis will be used to determine its value to more precisely measure plexiform neurofibromas. If the plexiform neurofibromas are increasing in size, the patient will be switched to the other treatment (from placebo to R115777 or vice versa). The design of this study is complicated but will hopefully offer the best chance of determining if R115777 is of benefit for progressive plexiform neurofibromas.