A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas

Inclusion Criteria: all patients (stratum 1 and 2): * All patients must have the clinical diagnosis of NF1 using the NIH Consensus Conference criteria. * Six or more café-au-lait spots (greater than or equal to 0.5 cm in prepubertal subjects or greater than or equal to 1.5 cm in postpubertal subjects). * Freckling in the 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. * Patients must have plexiform neurofibroma(s) 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. Patients with paraspinal plexiform neurofibromas will be eligible for this trial. 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 plexiform neurofibroma is clinically suspected. * Age: Patients must be greater than or equal to 3 years of age at the time of study entry. * Durable Power of Attorney: Adults evaluated for this study will be offered a durable power of attorney. Adults who are unable to provide informed consent will have to have a durable power of attorney in order to participate in this trial. * Disease status: Measurable disease: Patients must have measurable plexiform neurofibroma(s) amenable to volumetric MRI analysis. For the purpose of this study, a measurable lesion will be defined as a lesion of at least 3 cm measured in one dimension. * Performance Level: Karnofsky greater than or equal to 50% for patients \> 10 years of age and Lansky greater than or equal to 50 for patients less than or equal to 10 years of age (Appendix IV). Note: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. * Prior Therapy: Patients who underwent surgery for a progressive plexiform neurofibroma will be eligible to enter the study after the surgery, provided the plexiform neurofibroma was incompletely resected and is measurable. Patients are only eligible if complete resection of a plexiform neurofibroma with acceptable morbidity is not feasible, or if a patient with surgical option refuses surgery. Patients may have been previously treated for a plexiform neurofibroma but must have fully recovered from the acute toxic effects of all prior chemotherapy or radiotherapy prior to entering this study. * a. Myelosuppressive chemotherapy: Must not have received within 4 weeks of entry onto this study. * b. Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor that supports platelet, red or white cell number or function. * c. Biologic (anti-neoplastic agent): At least 14 days since the completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 14 days after administration, this period must be extended beyond the time during which adverse events are known to occur. These patients must be discussed with the Study Chair on a case-by-case basis. * d. Investigational Drugs: Patients must not have received an investigational drug within 4 weeks. * e. Steroids: Patients with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if necessary. * f. CYP3A4 inhibitors: Patients may not be currently receiving strong inhibitors of CYP3A4, and may not have received these medications within 1 week of entry. These include: Macrolide Antibiotics: clarithromycin, telithromycin, erythromycin, troleandomycin; Gastrointestinal prokinetic agents: cisapride, metoclopramide; Antifungals: itraconazole, ketoconazole, fluconazole, voriconazole, clotrimazole; Calcium channel blockers: verapamil, diltiazem, nicardipine; and, Other drugs: rifampin, bromocriptine, cimetidine, danazol, cyclosporine oral solution. * Grapefruit juice. * g. CYP3A4 inducers: Patients must also avoid strong inducers of CYP3A4 and may not have received these medications within 1 week of entry. These include: Anticonvulsants: carbamazepine, phenobarbital, phenytoin; Antibiotics: rifabutin, rifapentine; Herbal preparations: St. John's wort (Hypericum perforatum, hypericine). * h. Enzyme inducing anticonvulsants : Patients may not be taking enzyme - inducing anticonvulsants, and may not have received these medications within 1 week of entry, as these patients may experience different drug disposition. These medications include: Carbamazepine (Tegretol), Felbamate (Felbtol), Phenobarbitol, Phenytoin (Dilantin), Primidone (Mysoline), Oxcarbazepine (Trileptal), and, Herbal preparations: St. John's wort (Hypericum perforatum, hypericine). * i. XRT: Greater than or equal to 6 months from involved field radiation to index plexiform neurofibroma(s); greater than or equal to 6 weeks must have elapsed if patient has received radiation to areas outside index plexiform neurofibroma(s). * j. Surgery: At least 2 weeks since undergoing any major surgery. * Organ Function Requirements; Adequate Bone Marrow Function Defined as: Peripheral absolute neutrophil count (ANC)greater than or equal to 1500/μL; Platelet count greater than or equal to 100,000/μL (transfusion independent); and Hemoglobin greater than or equal to 10.0 gm/dL (may receive RBC transfusions). * Adequate Renal Function Defined as: A serum creatinine based on age, OR a creatinine clearance or radioisotope GFR greater than or equal to 70ml/min/1.73 m2 * Adequate Liver Function Defined As: Bilirubin (sum of conjugated + unconjugated) \< or equal to 1.5 x upper limit of normal (ULN) for age, and SGPT (ALT)\< or equal to 5 x upper limit of normal (ULN) for age, and Serum albumin \> or equal to 2 g/dL. * Fasting LDL Cholesterol: Patients must have a fasting LDL cholesterol of \< 160 mg/dL; Patients taking a cholesterol lowering agent must be on a single medication and on a stable dose for at least 4 weeks Specific eligibility criteria stratum 1 Disease status: \- Patients must have a progressive plexiform neurofibroma(s). Progression at the time of study entry is defined as: Presence of new plexiform neurofibromas on MRI or CT, OR A measurable increase of the plexiform neurofibroma (\> or equal to 20% increase in the volume, or a \> or equal to 13% increase in the product of the two longest perpendicular diameters, or a \> or equal to 6% increase in the longest diameter) over the last two consecutive scans (MRI or CT), or over the time period of approximately one year prior to evaluation for this study. Specific eligibility criteria stratum 2 Disease status: \- Radiographic disease progression as defined in Section 4.2.1 is not required for trial entry. Exclusion Criteria:(Both Strata): * Chronic treatment with systemic steroids or another immunosuppressive agent. * Patients with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if necessary. * Evidence of an active optic glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancer requiring treatment with chemotherapy or radiation therapy. Patients not requiring treatment are eligible for this protocol. * Dental braces or prosthesis that interfere with volumetric analysis of the neurofibroma(s). * Other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe infection, severe malnutrition, chronic liver or renal disease, active upper GI tract ulceration). * A known history of HIV seropositivity or known immunodeficiency. HIV testing will not be required as part of this trial, unless HIV is clinically suspected. * Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of sirolimus (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). A nasogastric tube (NG tube) is allowed. * Women who are pregnant or breast feeding. * Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method during the period they are receiving the study drug and for 3 months thereafter. Abstinence is an acceptable method of birth control. Women of childbearing potential will be given a pregnancy test within 7 days prior to administration of sirolimus and must have a negative urine or serum pregnancy test. * Patients who have received prior treatment with an mTOR inhibitor. * History of noncompliance to medical regimens. * Patients unwilling to or unable to comply with the protocol, or who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study. * Patients who have an uncontrolled infection.