This study will determine the optimal dose of the drug pirfenidone for treating children and young adults with neurofibromatosis type 1 (NF1). It will examine how the body handles the drug, treatment side effects, and whether pirfenidone can shrink or slow the growth of plexiform neurofibromas. Surgery is the only effective treatment for plexiform tumors, which arise from nerve. Often, however, not all the tumors can be removed, because of their number or location. Pirfenidone is effective in treating various fibrosing (scarring) conditions. Because the drug targets the same growth factors that are present in plexiform neurofibromas, it may also be effective in controlling tumors in patients with NF1.

Patients between 3 and 21 years of age with NF1 and plexiform neurofibromas may be eligible for this study. Patients whose tumors can easily be removed surgically may not participate in this study. Candidates will have a medical history and physical examination, blood and urine tests, and magnetic resonance imaging (MRI).

Study participants will take pirfenidone by mouth 3 times a day every day for 28 days. This constitutes one 28-day treatment cycle. The drug dose will be gradually increased in successive groups of three to six patients. Each group of patients must complete a 28-day cycle with no severe side effects before the next group receives a higher dose. The dose will continue to be increased until an effective dose in adults is reached. Treatment may continue for up to 2 years as long as the tumor remains stable or shrinks and side effects are tolerated. Patients (or their parents) will keep a record of treatment side effects and other medications taken.

Blood tests to monitor drug side effects will be done before cycles 2, 3, 4, 7, and 10, and at 6-cycle intervals after that. Physical examinations will be done at the same times, but at 3-cycle intervals after cycle 10. MRI scans will be done before treatment starts, again before cycle 4, and every six cycles after that to measure the size of the tumors. On the first day of treatment, patients will take only one dose of pirfenidone and will have a series of blood tests to measure blood levels of drug at various times. Blood samples of less than a teaspoon will be drawn at 1, 2, 3, 5, 8, 12, 24, and 24.5 hours after the pirfenidone dose. A small indwelling tube will be placed in the vein to avoid multiple needle sticks for the frequent draws. Tumor tissue samples may also be obtained from patients scheduled to have a biopsy (surgical removal of a sample of tumor tissue for examination) or surgery as part of their medical management. The samples will be analyzed for cell components of plexiform neurofibromas. Some of the tissue may be grown in culture to study what patients might be likely to benefit from treatment.

Patients (or their parents) will also be asked to fill out questionnaires assessing quality of life before starting treatment with pirfenidone, before treatment cycle 4, and then at 6-cycle intervals.

Condition	Treatment or Intervention	Phase
Neurofibromatosis 1 Plexiform Neurofibroma	Drug: Pirfenidone	Phase I

Further Study Details: 

Expected Total Enrollment:  18

Neurofibromatosis Type 1 (NF1) is an autosomal dominant, progressive genetic disorder characterized by diverse clinical manifestations. Patients with NF1 have an increased risk of developing tumors of the central and peripheral nervous system including plexiform neurofibromas (PNs), which may cause severe morbidity and possible mortality. The histopathology of these tumors suggests that events connected with formation of fibroblasts might constitute a point of molecular vulnerability. Gene profile analysis demonstrates overexpression of fibroblast growth factor, epidermal growth factor, and platelet-derived growth factor in PNs in patients with NF1. Pirfenidone is a novel anti-fibrotic agent that inhibits these and other growth factors. Clinical experience in adults has demonstrated that pirfenidone is effective in a variety of fibrosing conditions and pirfenidone is presently under study in a phase II trial for adults with progressive PNs. There are no data concerning the toxicity or efficacy of pirfenidone in children. A phase I trial of pirfenidone will be performed in children with NF1 and plexiform neurofibromas to determine the maximum tolerated dose or 'comparable dose', toxicities, and pharmacokinetics of pirfenidone. Pirfenidone will be administered orally three times a day (q8h) for cycles of 28 days with no rest period.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
Age: greater than or equal to 3 years and less than or equal to 21 years of age. Required body surface area (BSA) for first dose level (750 mg/m(2)/day) 0.61 m (2), for second dose level (1500 mg/m(2) /day) 0.31 m(2).
Diagnosis: Patients with NF1 and 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) or significant cosmetic problems, 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: 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.
Prior therapy: Patients must not have plexiform neurofibromas that can be easily surgically removed.
Patients must have recovered from the toxic effects of all prior therapy before entering this study. Recovery is defined as a toxicity grade less than 2.
Patients must have had their last dose of radiation therapy to the site of the plexiform neurofibroma at least 90 days prior to study entry, and their last dose of chemotherapy, immunotherapy, or hormonal therapy directed to the tumor, at least 30 days prior to study entry.
Performance Status: Patients greater than 10 years must have a Karnofsky performance level greater than or equal to 50, and children less than or equal to 10 years must have a Lansky performance level greater than or equal to 50. 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.
Hepatic Function: Patients must have a bilirubin within normal limits and SGPT less than or equal to 2 x upper limit of normal.
Renal Function: Patients must have an age-adjusted normal serum creatinine OR a creatinine clearance greater than or equal to (70 mL/min/1.73m(2)).
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 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 risks of this study before any protocol related studies are performed (other than the studies which were performed to determine patient eligibility).
Patients must be able to take pirfenidone by mouth. Capsules can be opened and content mixed with food for easier consumption in small children.
Patients (both male and female) must be willing to practice birth control (including abstinence) during and for two months after treatment, if of a child-bearing age. For purposes of this protocol, all patients greater than 9 years of age or those showing pubertal development will be considered of childbearing age.
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 judgment of the Principal or Associate Investigator would compromise the patients ability to tolerate pirfenidone or are likely to interfere with the study procedures or results.
Evidence of an active optic glioma requiring treatment with chemotherapy or radiation therapy or malignant glioma or a history of malignant peripheral nerve sheath tumor or other cancer.
An investigational agent within the past 30 days.
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.
Prior treatment with pirfenidone.

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States

Study ID Numbers:  030058; 03-C-0058
Record last reviewed:  November 4, 2004
Last Updated:  November 23, 2004
Record first received:  December 9, 2002
ClinicalTrials.gov Identifier:  NCT00050453
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08