This study will examine whether the experimental drug R115777 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 neurofibrin. Neurofibrin is thought
to help control the activity of another protein, called ras, which regulates cell growth.
Too little neurofibrin, 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 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 constituitively
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.
- INCLUSION CRITERIA:
Age: 3 years and 25 years of age.
Diagnosis: Patients with 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 (NIH Consensus Conference):
1. Six or more cafe-au-lait spots (0.5 cm in prepubertal subjects or 1.5 cm in
2. Freckling in the axilla or groin;
3. Optic glioma;
4. Two or more Lisch nodules;
5. A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of
long bone cortex);
6. 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: Patietns 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:
1. 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 (MRI or CT), or
over the time period of approximately one year prior to evaluation for this study.
2. 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
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: ?? ctep.cancer.gov. Recovery is defined as
a toxoicity grade less than 2, unless otherwise specified in the Inclusion and
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 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 ECOG performance score of 0, 1, or 2. Patients who are wheelchair bound because
of paralysis should be considered 'ambulatory' when they are up in their wheelchair.
Hematologic Function: Patients must have an absolute granulocyte count 1,500/ uL,
9.0 gm/dl, and a platelet count 150,000/uL at study entry, and a normal fibrinogen.
Hepatic Function: Patients must have a bilirubin within normal limits and SGPT 2x
upper limit of normal. Patients with Gilbert syndrome are excluded from the
requirement of a normal bilirubin. (Gilbert syndrome is found in 3-10% of the general
population, and is characterized by mild, chronic unconjugated hyperbilirubinemia in
the absence of liver disease or overt hemolysis).
Renal Function: Patients must have an age-adjusted normal serum creatinine OR a
creatinine clearance (70 mL / min / 1.73 m2).
Informed Consent: All patients or their legal guardians (if the patient is less than
18 years old) must sign an IRB approved document of informed consent (screening
protocol) prior to performing studies obtained exclusively to determine patient
eligibility. After confirmation of patient eligibility all patients or their legal
guardians must sign the protocol specific informed consent to document their
understanding of the investigational nature and the risk of this study before any
protocol related studies are performed (other than the studies which were performed
to determine patient eligibility). When appropriate pediatric patients will be
included in all discussion. Per institutional guidlines, age appropriate assent forms
for children from 7 through 12 years, and for children may be developed and, ehen
appropriate, will be signed by the pediatric patients in order to obtain written
Durable Power of Attorney (DPA):
All patients 18 years of age will be offered the opportunity to assign DPA so that
another person can make decisions about their medical care if they become
incapacitated or cognitively impaired.
Ability to undergo MRI examinations.
Pregnant or breast feeding females are excluded, because the toxic effects and
pharmacology of R115777 in the fetus and newborn are unknown.
Clinically significant unrelated systemic illness (serious infections or significant
cardiac, pulmonary, hepatic or other organ dysfunction) which in the judgement of the
Principal or Associate Investigator would compromise the patient's ability to
tolerate R115777 or are likely to interfere with the study procedures or results.
Prior treatment with greater than 1 prior myelosuppressive chemotherapy regimen.
An investigational agent within the past 30 days.
Evidence of an optic glioma, malignat glioma, malignant peripheral nerve sheath tumor
or other cancer requiring treatment with chemotherapy or radiation therapy.
Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor, or
Inability to return for follow-up visits or obtain follow-up studies required to
assess toxicity and response to therapy.
Prior treatment with R115777.