Phase 2 N=62 Randomized Single-blind Prevention

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

Neurofibroma, Plexiform · Neurofibromatosis Type I

Bottom Line

View on ClinicalTrials.gov: NCT00021541 ↗

Enrolled (actual)

Serious AEs

15.0%

Results posted

Sep 2012

Primary outcome: Primary: Median Time to Progression — 10.6; 14.5; 19.2; 13.3 Months

Study Design & Population

Study type: Interventional
Phase: Phase 2
Interventions: tipifarnib (Drug); placebo (Other)
Age: Pediatric, Adult · 3+ yrs
Sex: All
Sponsor: National Cancer Institute (NCI)
Primary completion: Feb 2009

Outcome Measures

Outcome	Result	p-value
PRIMARY Median Time to Progression	10.6; 14.5; 19.2; 13.3	—
PRIMARY Number of Participants With Adverse Events	59	—
SECONDARY Quality of Life (QOL)	3.69; 3.70; 3.91; 3.68	0.012 sig

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.

Eligibility Criteria

INCLUSION CRITERIA:

Age: 3 years and 25 years of age.

Diagnosis: Patients with neurofibromatosis type 1 (NF1) and progressive plexiform neurofibromas that have the potential to cause significant morbidity, such as (but not limited to) head and neck lesions that could compromise the airway or great vessels, brachial or lumbar plexus lesions that could cause nerve compression and loss of function, lesions that could result in major deformity (e.g., orbital lesions), lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions.

Histologic confirmation of tumor is not necessary in the presence of consistent clinical and radiographic findings, clinically suspected.

In addition to plexiform neurofibroma(s), all study subjects must have at least one other diagnostic criteria for NF1 listed below (National Institutes of Health (NIH) Consensus Conference[9]):

Six or more cafe-au-lait spots (0.5 cm in prepubertal subjects or 1.5 cm in postpubertal subjects).
Freckling in the axilla or groin;
Optic glioma;
Two or more Lisch nodules;
A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex);
A first degree relative with NF1.

In this study a plexiform neurofibroma is defined as a neurofibroma that has grown along the length of a nerve and may involve multiple fascicles and branches.

A spinal plexiform neurofibroma involves two or more levels with connection between the levels or extending laterally along the nerve.

Measurable disease: Patients must have measurable plexiform neurofibroma(s). For the purpose of this study a measurable lesion will be defined as a lesion of at least 3 cm measured in one dimension.

There must be evidence of recurrent or progressive disease as documented by an increase in size or the presence of new plexiform neurofibromas on MRI. Progression at the time of study entry is defined as:

A measurable increase of the plexiform neurofibroma (20% increase in the volume, or a 13% increase in the product of the two longest perpendicular diameters, or a 6% increase in the longest diameter) over the last two consecutive scans (magnetic resonance imaging (MRI) or computed tomography (CT)), or over the time period of approximately one year prior to evaluation for this study.
Patients who underwent surgery for a progressive plexiform neurofibroma will be eligible to enter the study after the surgery, provided the plexiform neurofibroma was incompletely resected and is measurable.

Prior therapy: Patients with NF1 are eligible at the time of recurrence or progression of inoperable plexiform neurofibroma.

A surgical consultation should be obtained prior to enrollment on the study to evaluate if tumor resection is a feasible option.

Patients will only be eligible if complete tumor resection is not feasible, or if a patient with surgical option refuses surgery.

Since there is no standard effective chemotherapy for patients with NF1 and progressive plexiform neurofibromas, patients may be treated on this trial without having received prior therapy.

Patients must have recovered from the toxic effects of all prior therapy before entering this study.

The Cancer Therapy Evaluation Program Common Toxicity Criteria (CTC) Version 2.0 will be used for toxicity assessment.

A copy of the CTC version 2.0 can be downloaded from the CTEP home page: http://ctep.cancer.gov. Recovery is defined as a toxicity grade less than 2, unless otherwise specified in the Inclusion and Exclusion Criteria.

Patients must have had their last dose of radiation therapy at least six weeks prior to study entry, and their last dose of chemotherapy at least four weeks prior to study entry.

Patients who received growth colony stimulating factor (G-CSF) after the prior cycle of chemotherapy must be off G-CSF for at least one week prior to entering this study.

Performance Status: Patients should have a life expectancy of at least 12 months and an E

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Data sourced from ClinicalTrials.gov (NCT00021541). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.