Inclusion Criteria

- INCLUSION CRITERIA:

INCLUSION CRITERA FOR ALL PATIENTS (STRATUM 1 AND 2):

All patients must have the clinical diagnosis of NF1 using the NIH Consensus Conference
criteria. In addition to a plexiform neurofibroma, one or more of the following diagnostic
criteria for NF1 must be present:

- Six or more cafe-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 percent for patients greater than
10 years of age and Lansky greater than or equal to 50 for patients less than or equal to
10 years of age. 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.

- Myelosuppressive chemotherapy: Must not have received within 4 weeks of entry onto
this study.

- 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.

- 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.

- Investigational Drugs: Patients must not have received an investigational drug within
4 weeks.

- Steroids: Patients with endocrine deficiencies are allowed to receive physiologic or
stress doses of steroids if necessary.

- 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

- Other drugs: rifampin, bromocriptine, cimetidine (tagamet), danazol,
cyclosporine oral solution, lansoprazole (prevacid)

- Grapefruit juice.

- 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).

- 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)

- 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).

- 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/miroL

- Platelet count greater than or equal to 100,000/micorL (transfusion independent)

- 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 as follows:

- Less than or equal to 5 years old, Maximum Serum Creatinine (mg/dL) 0.8

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

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

- Greater than 15 years old Maximum Serum Creatinine (mg/dL) 1.5

OR a creatinine clearance or radioisotope GFR greater than or equal to 70ml/min/1.73 m(2)

- Adequate Liver Function Defined As:

- Bilirubin (sum of conjugated plus unconjugated) less than or equal to1.5 times
upper limit of normal (ULN) for age, and

- SGPT (ALT) less than or equal to 5 times upper limit of normal (ULN) for age,
and

- Serum albumin greater than or equal to 2 g/dL.

- Fasting LDL Cholesterol:

- Patients must have a fasting LDL cholesterol of less than or equal to 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 (documented by comparison
with prior MRI or CT), OR

- A measurable increase of the plexiform neurofibroma (greater than or equal to 20
percent increase in the volume, or a greater than or equal to 13 percent
increase in the product of the two longest perpendicular diameters, or a greater
than or equal to 6 percent increase in the longest diameter) documented by
comparison of two scans (MRI or CT) in the time period of approximately one year
or less prior to evaluation for this study.

SPECIFIC ELIGIBILITY CRITERIA STRATUM 2

Disease status:

- No radiographic disease progression as defined for criteria stratum 1 (above) by
comparison of two scans (MRI or CT) in the time period of approximately one year +/-
one month.

EXCLUSION CRITERIA:

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.