Neoplasms

Nervous System Diseases

Diseases and Abnormalities at or Before Birth

All Conditions

Symptoms and General Pathology

Skin and Connective Tissue Diseases

Rare Diseases

Neurofibromatoses

Neurofibromatosis 1

Neurofibroma

Neurofibroma, Plexiform

Nerve Sheath Neoplasms

Neoplasms, Nerve Tissue

Neoplasms by Histologic Type

Syndrome

Neoplastic Syndromes, Hereditary

Neurocutaneous Syndromes

Heredodegenerative Disorders, Nervous System

Neurodegenerative Diseases

Genetic Diseases, Inborn

Peripheral Nervous System Diseases

Neuromuscular Diseases

Nervous System Neoplasms

Peripheral Nervous System Neoplasms

Oculocerebral Syndrome With Hypopigmentation

Neurofibromatosis

Neurofibromatosis Type 1

Antineoplastic Agents

All Drugs and Chemicals

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.

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.

Given orally, 200 mg/m\^2/dose BSA every 12 hours by mouth (po) daily x 21 days, Course is every 28 days

tipifarnib

Patients receive oral placebo every 12 hours on days 1-21. Courses repeat as in arm I.

placebo

Brigitte Widemann, M.D.

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.

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.

R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas

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 is defined as ≥20% increase in diameter based on volumetric analysis using the 1-dimensional RECIST method. Start of phase A or phase B to time of progression.

Median time to progression is defined as ≥25% increase in area based on volumetric analysis using the 2-dimensional WHO solid tumor method.

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.

Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

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.

National Cancer Institute (NCI)

Principal Investigator

Adverse event data is in compliance with DSMB(Data Safety Monitoring Board).

Patients receive oral tipifarnib every 12 hours on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients receive oral placebo every 12 hours on days 1-21. Courses repeat as in arm I.

Tipifarnib & Placebo

Patients receive oral tipifarnib every 12 hours on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. These are the patients that started on tipifarnib only. This number does not reflect the total amount of patients that crossed over to placebo.

Phase A-Tipifarnib

Patients receive oral placebo every 12 hours on days 1-21. Courses repeat as in arm I. These are the patients that started on placebo only. This number does not reflect the total amount of patients that crossed over to tipifarnib. Two of the 31 patients were deemed ineligible, thus 29 started placebo.

Phase B - Placebo

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

American Indian or Alaska Native

Asian

Native Hawaiian or Other Pacific Islander

Black or African American

White

More than one race

Unknown or Not Reported

Hispanic

Race/Ethnicity, Customized

United States

Region of Enrollment

Placebo

Phase A - Tipifarnib

phase A - 62 started and 2 were ineligible = 60 phase B - 43 started

Median Time to Progression

Adverse event data is in compliance with DSMB (Data Safety Monitoring Board).

Number of Participants With Adverse Events

Baseline

Pre cycle 4

Patients receive oral tipifarnib every 12 hours on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Participants analyzed includes only those whose parents completed the IPI Scale at baseline and pre cycle 4 on phase A.

Quality of Life (QOL)

Phase B - Placebo group is not shown because this outcome measure only applies to the Phase A - Tipifarnib group.

Median Time to Progression Using the Conventional 1-Dimensional Response Evaluation Criteria in Solid Tumors (RECIST) Method

Phase B- Placebo group is not shown because this outcome measure only applies to the Phase A - Tipifarnib group.

Median Time to Progression Using the 2-Dimensional World Health Organization (WHO) Solid Tumor Method

Patients receive oral tipifarnib every 12 hours on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.Patients receive tipifarnib ONLY in the first treatment until they progress to the second treatment/crossover to receive placebo.

Phase A -Tipifarnib

Patients receive oral placebo every 12 hours on days 1-21. Courses repeat as in arm I.Patients receive placebo ONLY in the first treatment until they progress to the second treatment/crossover to receive tipifarnib.

Spots Global Cancer Trial Database for natural history of neurofibromatosis type 1 (nf1)