Pirfenidone in Treating Young Patients With Neurofibromatosis Type 1 and Plexiform Neurofibromas

OBJECTIVES:

• Determine the maximum tolerated dose or "comparable dose" of pirfenidone in pediatric patients with neurofibromatosis type 1 and inoperable, symptomatic plexiform neurofibromas.
• Determine the toxic effects of this drug in these patients.
• Determine the plasma pharmacokinetics of this drug in these patients.
• Determine, preliminarily, if this drug could be beneficial for pediatric patients with refractory solid tumors.
• Assess the quality of life of patients treated with this drug.

OUTLINE: This is an open-label, multicenter, dose-escalation study.

Patients receive oral pirfenidone three times daily on days 1-28. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of pirfenidone until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Quality of life is assessed at baseline, before course 4, and then after every 6 courses.

PROJECTED ACCRUAL: A total of 3-18 patients will be accrued for this study within 18 months.

DISEASE CHARACTERISTICS:

• Diagnosis of neurofibromatosis type 1 (NF1) AND
• Plexiform neurofibromas

• Neurofibromas that have grown along the length of a nerve and may involve multiple fascicles and branches (spinal neurofibromas involve 2 or more levels with connection between the levels or extending laterally along the nerve)
• Potential to cause significant morbidity such as:

• Head and neck lesions that could compromise 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
• Painful lesions
• Meets at least 1 other diagnostic criteria for NF1

• 6 or more cafe-au-lait spots (at least 0.5 cm in prepubertal patients or at least 1.5 cm in postpubertal patients)
• Freckling in the axilla or groin
• Optic glioma
• 2 or more Lisch nodules
• Distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex)
• First-degree relative with NF1
• Measurable plexiform neurofibromas

• At least 3 cm in 1 dimension
• Tumor resection not feasible
• No history of malignant peripheral nerve sheath tumor or other cancer
• No evidence of an active optic glioma requiring chemotherapy or radiotherapy
• No malignant glioma

PATIENT CHARACTERISTICS:

Age

• 3 to 21

Performance status

• Karnofsky 50-100% (over 10 years of age)
• Lansky 50-100% (10 years and under)

Life expectancy

• Not specified

Hematopoietic

• Absolute granulocyte count at least 1,500/mm^3
• Hemoglobin at least 9.0 g/dL
• Platelet count at least 150,000/mm^3

Hepatic

• Bilirubin normal
• SGPT no greater than 2 times upper limit of normal
• No clinically significant hepatic dysfunction that would preclude study participation

Renal

• Creatinine normal for age OR
• Creatinine clearance at least 70 mL/min

Cardiovascular

• No clinically significant cardiac dysfunction that would preclude study participation

Pulmonary

• No clinically significant pulmonary dysfunction that would preclude study participation

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 2 months after study
• Must be able to take pirfenidone orally
• No serious infections
• No clinically significant unrelated systemic illness or organ dysfunction that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• At least 30 days since prior immunotherapy
• No concurrent immunotherapy
• No concurrent hematopoietic growth factors

Chemotherapy

• At least 30 days since prior chemotherapy
• No concurrent chemotherapy directed at the tumor

Endocrine therapy

• At least 30 days since prior hormonal therapy directed at the tumor
• No concurrent hormonal therapy directed at the tumor

Radiotherapy

• At least 90 days since prior radiotherapy to the site of the plexiform neurofibroma
• No concurrent radiotherapy directed at the tumor

Surgery

• Not specified

Other

• Recovered from prior therapy
• More than 30 days since prior investigational agents
• No prior pirfenidone
• No other concurrent investigational agents