Sorafenib to Treat Children and Young Adults With Neurofibromatosis Type 1 and Inoperable Plexiform Neurofibromas

1. Age: greater than or equal to 3 years and less than or equal to 18 years of age at the time of study enrollment. The upper age limit is in place because early childhood and puberty are considered to be the greatest risk for disease progression, and where sorafenib may have the most benefit. In addition, an important objective of this study is to characterize the pharmacokinetics of sorafenib in the pediatric population since it has been well studied in adults.

2. Diagnosis: Patients with NF1 and inoperable PNs 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. 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.

   A PN is defined as a neurofibroma that has grown along the length of a nerve and may involve multiple fascicles and branches. A spinal PN involves two or more levels with connection between the levels or extending laterally along the nerve. In addition to PN, all study subjects must have either positive genetic testing for NF1 or have at least one other diagnostic criterion for NF1 listed below (NIH Consensus conference:

   • Six or more cafe-au-lait spots (greater than or equal to 0.5cm in prepubertal subjects or greater than or equal to 1.5 cm in post pubertal subjects)
   • Freckling in axilla or groin
   • Optic glioma
   • Two or more Lisch nodules
   • A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex)
   • A first-degree relative with NF1
3. Measurable disease: Patients must have at least one measurable PN, defined as a lesion of at least 3 cm measured in one dimension. Patients who underwent surgery for resection of a PN are eligible provided the PN was incompletely resected and is measurable as per criteria above.

4. Prior Therapy: Patients with NF1 will only be eligible if complete tumor resection is not feasible, or if a patient with a surgical option refuses surgery.

   • Since there is no standard effective chemotherapy for patients with NF1 and PN, patients may be treated on this trial without having received prior medical therapy directed at their PN.
   • May have received less than or equal to 1 myelosuppressive regimen for PN or other tumor manifestations associated with NF1 such as optic glioma.
   • Patients who have received previous investigational agents or biologic therapy, such as tipifarnib, pirfenidone, Peg-Intron, or other VEGFR inhibitors are eligible for enrollment.
   • Growth factors that support platelet or white cell number or function must not have been administered within the past 7 days.
   • Patients who received prior medical therapy for their PN must have recovered from the toxic effects of all prior therapy before entering this study.
5. Performance status: Patients greater than 10 years of age must have a Karnofsky performance level of greater than or equal to 50%, and children less than or equal to 10 years old must have a Lansky performance of greater than or equal to 50% (Appendix I).
6. Hematologic Function: Patients must have an absolute neutrophil count greater than or equal to 1500/microl, hemoglobin greater than or equal to 9g/dl, and platelet greater than or equal to 100,000/microl.
7. Coagulation: Patients must have adequate hemostatic function defined as PT and PTT less than or equal to 1.5 times ULN. Patients receiving prophylactic anticoagulation for thrombosis are eligible if they meet criteria for adequate hemostatic function (PT and PTT less than or equal to 1.5 times ULN) and thrombotic episode occurred 3 months prior to enrollment. Use of anticoagulants or thrombolytics for care and maintenance of central venous catheters is acceptable.
8. Hepatic Function: Patients must have bilirubin within the upper limit of normal for age, and ALT within the upper limit of normal for age.
9. Serum lipase and amylase within upper limits of normal.

10. Renal Function: Patients must have a creatinine clearance or radioisotope GFR greater than or equal to 60ml/min/1.73 m(2) or a normal serum creatinine based on age described in the table below.

    Age (years) less than or equal to 5 Maximum Serum Creatinine (mg/dL) 0.8

    Age (years) 5 less than or equal to 10 Maximum Serum Creatinine (mg/dL) 1.0

    Age (years) 10 less than or equal to 15 Maximum Serum Creatinine (mg/dL) 1.2

    Age (years) greater than 15 Maximum Serum Creatinine (mg/dL) 1.5

11. Blood pressure: Patients must have a systolic and diastolic blood pressure less than 95th percentile for age and gender (Appendix II) measured as described in section 2.2.
12. Informed Consent: Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial must only be done after obtaining written informed consent from all patients or their legal guardians (if the patient is less than 18 years old). When appropriate, pediatric patients will be included in all discussions. This can be accomplished through one of the following mechanisms: a) the NCI, POB screening protocol, b) an IRB-approved institutional screening protocol or c) the study-specific protocol. Documentation of the informed consent for screening will be maintained in the patient s research chart. Studies or procedures that were performed for clinical indications (not exclusively to determine eligibility) may be used for baseline values even if the studies were done before informed consent was obtained.
13. Durable Power of Attorney (DPA): All patients greater than 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.

EXCLUSION CRITERIA:

1. Pregnant or breast-feeding females are excluded due to risks of fetal and teratogenic adverse events as seen animal studies. Pregnancy tests must be obtained prior to enrollment on this study in girls, age 9 or older. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. Abstinence is an acceptable method of birth control.
2. Sorafenib is predominantly metabolized via CYP3A4, and patients who take cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine or Phenobarbital), rifampin, grape fruit, or St. Johns Wort will not be eligible for the trial. Patients must have discontinued these medications at least 7 days prior to enrollment of trial.
3. Patients who have had major surgery within the past 3 months are excluded. Patients having minor surgery (i.e., central line placement) within the past 2 weeks are excluded.
4. An investigational agent within the past 30 days.
5. Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor, immunotherapy, or biologic therapy.
6. Clinically significant uncontrolled unrelated systemic illness such as serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction.
7. Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
8. Inability to swallow tablets, since tablets cannot be crushed or broken.
9. Inability to undergo MRI and/or contraindication for MRI examinations following the MRI protocol (Appendix III). Prosthesis or orthopedic or dental braces that would interfere with volumetric analysis of target PN on MRI.
10. Prior treatment with sorafenib.
11. Evidence of an optic glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancer requiring treatment with chemotherapy or radiation therapy.
12. Patients with a history of arterial or venous thrombosis with in the prior 3 months.
13. Patients who experienced significant hemorrhage (hemoptysis, melena, or hematemesis) within the past 2 weeks or with a history of bleeding diathesis.
14. Patients with a history of NF1 related cerebral vascular anomaly.
15. Patients requiring systemic full dose anticoagulation with systemic thrombolytics, heparin, coumadin, or low molecular weight heparin or other anticoagulants for therapy of active thrombosis within the prior 3 months.
16. Patients on anti-hypertensive medications and patients with baseline hypertension (greater than or equal to 95th % for age and gender, see Appendix II) (treated or untreated).