Know Cancer

forgot password

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

Phase 2
3 Years
25 Years
Not Enrolling
Neurofibroma, Plexiform, Neurofibromatosis Type I

Thank you

Trial Information

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

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.

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

1. Six or more cafe-au-lait spots (0.5 cm in prepubertal subjects or 1.5 cm in
postpubertal subjects).

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: 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:

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 (magnetic
resonance imaging (MRI) or computed tomography (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 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: 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 Eastern Cooperative Oncology Group (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 serum
glutamic pyruvic transaminase (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 m^2).

Informed Consent: All patients or their legal guardians (if the patient is less than
18 years old) must sign an institutional review board (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

When appropriate pediatric patients will be included in all discussion. Per
institutional guidelines, age appropriate assent forms for children from 7 through 12
years, and for children may be developed and, when appropriate, will be signed by the
pediatric patients in order to obtain written assent.

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, malignant 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.

Type of Study:


Study Design:

Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double-Blind, Primary Purpose: Prevention

Outcome Measure:

Median Time to Progression

Outcome Description:

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.

Outcome Time Frame:

8 years

Safety Issue:


Principal Investigator

Brigitte Widemann, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Insitutes of Health, National Cancer Institute


United States: Federal Government

Study ID:




Start Date:

July 2001

Completion Date:

November 2010

Related Keywords:

  • Neurofibroma, Plexiform
  • Neurofibromatosis Type I
  • Surrogate Markers
  • 3-Dimensional Magnetic Resonance Imaging (MRI)
  • Natural History of Neurofibromatosis Type 1 (NF1)
  • Tumor Tissue Bank
  • Neurofibromatosis
  • NF1
  • Neurofibromatosis Type 1
  • Plexiform Neurofibroma
  • Neurofibroma
  • Neurofibroma
  • Neurofibromatoses
  • Neurofibromatosis 1
  • Osteitis Fibrosa Cystica
  • Neurofibroma, Plexiform



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892
University of Alabama at Birmingham (M1149) Birmingham, Alabama  35233
Children's Hospital Los Angeles, CA (M1118) Los Angeles, California  90027
Children's Memorial Hospital, Chicago, IL (M1484) Chicago, Illinois  60614
Johns Hopkins Oncology Center (M1011) Baltimore, Maryland  21231
The Children's Hospital, Dana-Farber Cancer Institute, Boston, MA (M1034) Boston, Massachusetts  02115
St. Louis Children's Hospital, St. Louis, MO (M1123) St. Louis, Missouri  63110
SUNY Upstate Medical University, NY (M1303) Syracuse, New York  13210
Cincinnati Children's Hospital (FWA 00002988) Cincinnati, Ohio  45229
Childrens Hospital of Philadelphia, PA (M1257) Philadelphia, Pennsylvania  19104
Texas Children's Hospital, Houston, TX (M1060) Houston, Texas  77030