• Maximum tolerated dose and tolerability of sorafenib tosylate [ Designated as safety issue: Yes ]
  
• Toxicity according to NCI CTCAE v3.0 [ Designated as safety issue: Yes ]
  
• Bone toxicity as assessed by volumetric MRI analysis, height and growth measurement, dual-energy x-ray absorptiometry, and laboratory measurements for evaluation of bone turnover and metabolism [ Designated as safety issue: Yes ]
  

• PN growth rate as assessed by automated volumetric MRI analysis [ Designated as safety issue: No ]
  
• Adherence to chronic daily dosing with sorafenib as assessed by pill counts, adherence diaries and questionnaire forms [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary

• To determine the maximum tolerated dose (MTD), extended tolerability, and recommended phase II dose of sorafenib tosylate in patients with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN).
• To describe and define the toxicities of chronic dosing with this drug in these patients.
• To evaluate potential bone toxicities, such as growth plate expansion and growth retardation, using automated volumetric MRI analysis, multiple measures for height and growth, dual-energy x-ray absorptiometry for assessment of bone mineral density, and laboratory measurements for assessment of bone turnover and metabolism in these patients.

Secondary

• To determine the effect of this drug on the growth rate of PN in these patients using automated volumetric MRI analysis.
• To measure patient adherence to chronic dosing with this drug.

OUTLINE: This is a multicenter study.

Patients receive oral sorafenib tosylate twice daily on days 1-28. Patients with no documented disease progression or maximum radiographic response within the past 2 years continue treatment for up to 6 months in the absence of disease progression or unacceptable toxicity. All other patients continue treatment for as long as benefit is shown.

After completion of study therapy, patients are followed at 30 days.

DISEASE CHARACTERISTICS:

• Histologically confirmed* neurofibromatosis 1 (NF1) and plexiform neurofibromas (PNs) that are inoperable AND have the potential to cause significant morbidity including, but not limited to, any of the following:

  • 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
  • Painful lesions. NOTE: *Histologic confirmation of tumor is not necessary in the presence of consistent clinical and radiographic findings, but should be considered if malignant degeneration of a PN is clinically suspected.

• Must have either positive genetic testing for NF1 OR at least one other diagnostic criterion (according to NIH Consensus conference criteria), including any of the following:

  • Six or more café-au-lait spots (≥ 0.5cm in prepubertal patients or ≥ 1.5 cm in post pubertal patients)
  • Freckling in the axilla or groin
  • Optic glioma
  • Two 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 disease, defined as ≥ 1 unidimensionally measurable PN ≥ 3 cm

  • Patients who have undergone surgery for resection of a PN are eligible provided the PN was incompletely resected and is measurable as defined above
• Complete tumor resection is not feasible or patient refused surgery
• No evidence of an optic glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancer requiring treatment with chemotherapy or radiotherapy

PATIENT CHARACTERISTICS:

• Karnofsky performance status (PS) 50-100% (patients >10 years of age)
• Lansky PS 50-100% (patients ≤ 10 years of age)
• ANC ≥ 1,500/μL
• Platelet count ≥ 100,000/μL
• Hemoglobin ≥ 9 g/dL
• Adequate hemostatic function, defined as PT and PTT ≤ 1.5 times upper limit of normal (ULN)
• Bilirubin normal (in the absence of Gilbert syndrome)
• ALT normal
• Serum lipase and amylase normal

• Creatinine clearance or radioisotope glomerular filtration rate ≥ 60mL/ min OR serum creatinine normal based on age as follows:

  • 0.8 mg/dL (for patients 5 years of age and under)
  • 1.0 mg/dL (for patients 6 -10 years of age)
  • 1.2 mg/dL (for patients 11-15 years of age)
  • 1.5 mg/dL (for patients over 15 years of age)
• Not pregnant or nursing
• Negative pregnancy test for female patients 9 years of age and older
• Fertile patients must use effective contraception
• No clinically significant uncontrolled unrelated systemic illness such as serious infections or significant cardiac, pulmonary, hepatic, or other organ dysfunction
• Able to swallow tablets
• No inability to undergo MRI and/or contraindication for MRI examinations in accordance with the MRI protocol
• No patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study
• No arterial or venous thrombosis within the past 3 months
• No significant hemorrhage (i.e., hemoptysis, melena, or hematemesis) within the past 2 weeks
• No history of bleeding diathesis
• No history of NF1-related cerebral vascular anomaly
• No requirement for systemic full-dose anticoagulation with systemic thrombolytics, heparin, coumadin, or low molecular weight heparin or other anticoagulants for therapy of active thrombosis within the past 3 months
• No baseline hypertension (≥ 95th% for age and gender)

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Recovered from all prior therapy for PN
• No more than 1 prior myelosuppressive regimen for PN or other tumor manifestations associated with NF1 such as optic glioma
• Prior biologic therapy allowed (e.g., tipifarnib, pirfenidone, peg-Intron, or other VEGFR inhibitors)
• No prior sorafenib
• No prosthesis or orthopedic or dental braces that would interfere with volumetric analysis of target PN by MRI
• More than 3 months since prior major surgery
• More than 2 weeks since prior minor surgery (i.e., central line placement)
• More than 30 days since prior and no other concurrent investigational treatment
• More than 7 days since prior and no concurrent hematopoietic growth factors that support platelet or white cell number or function

• At least 7 days since prior and no concurrent cytochrome P450 enzyme-inducing antiepileptic drugs, including any of the following:

  • Phenytoin
  • Carbamazepine
  • Phenobarbital
  • Rifampin
  • Grapefruit
  • St. Johns wort (Hypericum perforatum)
• Concurrent prophylactic anticoagulation for thrombosis allowed provided patient has adequate hemostatic function and thrombotic episode occurred 3 months prior to study entry
• No other concurrent cancer chemotherapy, radiotherapy, hormonal therapy directed at the tumor, immunotherapy, or biologic therapy