Closed due to slow accrual prior to interim analysis.

This phase II trial is studying how well AZD2171 works in treating patients with neurofibromatosis type 1 and plexiform neurofibroma and/or neurofibroma near the spine. AZD2171 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

PRIMARY OBJECTIVES:

I. Assess the efficacy of AZD2171, in terms of volume change in target tumors by 3-dimensional magnetic resonance imaging (3D MRI).

II. Describe and define the toxicities of AZD2171 in these patients.

SECONDARY OBJECTIVES:

I. Assess the value of 3D MRI data analysis in evaluating plexiform or paraspinal neurofibromas compared to conventional 2-dimensional MRI data analysis.

II. Assess the value of delayed contrast-enhanced MRI (DCE-MRI) in determining changes in vascularity of neurofibromas before and during treatment. III. Assess the quality of life of patients treated with AZD2171. IV. Evaluate the effect of AZD2171 on biological changes of human neurofibroma by comparing pre- and post-treatment specimens from patients involved in this trial or, alternatively, by evaluating the effect of AZD2171 on human tumor grafts in experimental animals.

V. Evaluate relevant pharmacodynamic markers (circulating endothelial cells [CECs] and vascular endothelial growth factor-2 [VEGF2] levels) and pharmacogenetics analyses (variation in kdr/flk-1 and other genes) in response to AZD2171.

OUTLINE: This is a multicenter study. Patients are stratified according to tumor location (peripheral vs paraspinal plexiform neurofibroma). Patients receive oral AZD2171 once daily on days 1-28.

Treatment repeats every 28 days for 26 courses in the absence of disease progression or unacceptable toxicity. Patients with responding or stable disease may continue treatment beyond 26 courses in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at baseline, prior to course 2, prior to course 4, and every 6 courses thereafter.

Inclusion Criteria:

• Diagnosis* of neurofibromatosis type 1 (NF1) and extensive plexiform and/or paraspinal neurofibromasproducing pain (not controlled by use of over-the-counter medications), progressive neurologic deficit, or significant neurologic consequenceswith continuous tumor growth

  • Extensive paraspinal neurofibroma defined as a neurofibroma that involves multiple neural roots at ≥ 3 spinal levels with connection between the levels or extending laterally along the nerves

    • Symptomatic neurofibromas at < 3 spinal levels, but surgical treatment is not possible, allowed

• Meets ≥ 2 diagnostic criteria for NF1, including the following:

  • Six or more café-au-lait spots (≥ 1.5 cm in postpubertal patients)
  • Freckling in the axilla or groin
  • Optic glioma
  • Two or more Lisch nodules
  • Distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia orthinning of long-bone cortex)
  • First-degree relative with NF1

• Patients with documented mutation in neurofibromin gene with onlysymptomatic plexiform and/or paraspinal neurofibroma who do not fulfill the above clinical criteria are eligible

• Measurable disease, defined as ≥ 1 lesion whose longest diameter can beaccurately measured as 8.0 cm^3 with 3-dimensional (3D) MRI

  • Skin lesions are consideredmeasurable (e.g., plexiform neurofibromas), but MRI imaging still required for 3D measurement

• Patients with symptomatic neurofibroma, in whom surgery is not feasible, who refuse surgery or are not goodsurgical candidates due to high risk of damage to vital structures or spinal cordinjury are eligible

• No evidence of progressive optic glioma, malignant glioma, malignant peripheralnerve sheath tumor, or other cancer requiring treatment with chemotherapy orradiotherapy

• ECOG performance status 0-3

• WBC ≥ 3,000/mm^3

• Absolute neutrophil count ≥ 1,500/mm^3

• Platelet count ≥ 100,000/mm^3

• Hemoglobin ≥ 8.0 g/dL

• Bilirubin normal (patients with Gilbert's syndrome allowed despite elevated bilirubin)

• Alkaline phosphatase normal

• AST and ALT ≤ 2.5 times upper limit of normal

• Thyroid-stimulating hormone and free thyroxin normal

• Creatinine normal OR creatinine clearance ≥ 60 mL/min

• Ejection fraction ≥ 50% by echocardiogram

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No other uncontrolled, serious medical condition that would preclude study participation, including any of the following:

  • Cardiac arrhythmia
  • Diabetes
  • Serious infection
  • Significant cardiac, pulmonary, hepatic, or other organ dysfunction

• No psychiatric illness or social situation that would preclude study compliance

• No history of allergic reactions attributed to compounds of similar chemical orbiologic composition to AZD2171

• No New York Heart Association class III or IV disease

  • Class II disease controlled with treatment and increased monitoring allowed

• No systolic blood pressure (BP) > 130 mm Hg and diastolic BP > 90 mm Hg

• No history of familial long QT syndrome

• Mean QTc ≤ 470 msec (with Bazett's correction) by EKG

• QTc prolongation ≤ 500 msec

• No other significant ECG abnormality within the past 14 days

• See Disease Characteristics

• More than 30 days since prior investigational agents

• More than 4 weeks since prior radiotherapy, chemotherapy, hormonal therapy directed at thetumor, immunotherapy, biologic therapy (e.g., interferon), or majorsurgery

• No concurrent medication that may markedly affect renal function (e.g., vancomycin, amphotericin, or pentamidine)

• No concurrent CYP interactive medications

• No concurrent combination antiretroviral therapy for HIV-positive patients

• No concurrent enzyme-inducing anticonvulsants (e.g., phenytoin, carbamazepine, or phenobarbital)

• No concurrent use of drugs or biologics with proarrhythmic potential