Protocol Number: 01-C-0222

Title:

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

Number:

01-C-0222

Summary:

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 neurofibromin. Neurofibromin 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 will have a medical history and physical and eye examinations, blood and urine tests, and magnetic resonance imaging (MRI). Photographs will be taken of tumors visible on the body surface.

Study participants will be randomly assigned to receive either R115777 or placebo (an inactive substance). They will 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 will continue as long as the tumors remain stable or shrink and side effects are tolerable. The treatment will be switched (for example, from placebo to R115777) or stopped if the tumors grow and will be stopped if side effects are unacceptable. Patients (or their parents) will be asked to keep a record of side effects.

For the first 3 months of treatment, patients will have a physical examination and blood tests every other week. Blood tests will also be done before cycles 3, 6, 9 and 12 to measure protein levels and the level of a substance called nerve growth factor. MRI scans will be done periodically throughout treatment to measure the size of the tumors. Cells will be collected from inside the cheek before the first treatment dose and at one point in time after at least 14 days of treatment on each study phase (R115777 or placebo). A tissue biopsy (surgical removal of a small tumor tissue sample) will be requested before treatment begins and again at least 2 weeks after treatment starts, if tumor nodules are easily accessible for biopsy. Tumor samples may also be obtained from tissue removed from patients who must undergo surgery for medical management of their disease. The tissue samples will be analyzed for changes in the NF1 and ras genes and in the ras protein.

Patients (or their parents) will also be asked periodically throughout the course of treatment to fill out questionnaires assessing quality of life.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: Yes

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

Age greater than or equal to 3 years and less than or equal to 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.

In addition to plexiform neurofibroma (s), all study subjects must have at least one other diagnostic criteria for NF1 listed below:

1. Six or more cafe-au-lait spots (greater than or equal to 0.5 cm in prepubertal subjects or greater than or equal to 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.

Measurable disease: Patietns must have measurable plexiform neurofibroma(s) 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.

1. A measurable increase of the plexiform neurofibroma (greater than or equal to a 20% increase in the volume, or greater than or equal to a 13% increase in the product of the two longest perpendicular diameters, or greater than or equal to 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.

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

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.

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 greater than or equal to 1,500/microliters, a hemoglobin greater than or equal to 9.0 gm/dl and a platelet count greater than or equal to 150,000/microliters at study entry, and a normal fibrinogen.

Hepatic Function: Patients must have a bilirubin within normal limits and SGPT less than or equal to 2x upper limit of normal. Patients with Gilbert syndrome are excluded from the requirement of a normal bilirubin.

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 indicating their understanding of the investigational nature and the risks of this study BEFORE any protocol related studies are performed (this does not include routine laboratory tests or imaging studies required to establish eligibility). When appropriate pediatric patients will be included in all discussion in order to obtain verbal assent.

Durable Power of Attorney: All patients greater than or equal to 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.

EXCLUSION CRITERIA:

Pregnant or breast feeding females are excluded.

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 immunotherapy.

Inability to return for follow-up visits or obtain follow-up studies required to assess toxicity and response to therapy.

Concomitant use of, nexium pump inhibitors (e.g., omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole).

Prior treatment with R115777.

Special Instructions: Currently Not Provided

Keywords:

Surrogate Markers

3-Dimensional MRI

Natural History of NF1

Tumor Tissue Bank

Recruitment Keywords:

Neurofibromatosis

NF1

Neurofibromatosis Type 1

Plexiform Neurofibroma

Neurofibroma

Conditions:

Neurofibroma, Plexiform

Neurofibromatosis Type I

Investigational Drug(s):

R115777

Investigational Device(s):

None

Contacts:

Andrea F. Gillespie, R.N.
National Institutes of Health
Building 10
Room 13C013
10 Center Drive
Bethesda, Maryland 20892
Phone: (301) 402-1848
Fax: (301) 480-8871

Electronic Address: gillesan@exchange.nih.gov

Citations:

Neurofibromatosis type 1 and Ras-mediated signaling: filling in the GAPs

Patients treated with antitumor drugs displaying neurological deficits are characterized by a low circulating level of nerve growth factor

Neurofibromatosis type 1--an update and review for the primary pediatrician

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