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

Inclusion Criteria

• •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.
• •* 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.
• •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.