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Investigator(s):
Brigitte Widemann, M.D. Principal Investigator Phone: 301-496-7387 widemanb@pbmac.nci.nih.gov
Referral Contact(s):
Pediatric Oncology  Phone: 1-877-624-4878 (Toll free)

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Primary Eligibility:

• Clinical diagnosis* of neurofibromatosis type 1 (NF1), according to NIH Consensus Conference criteria, with plexiform neurofibromas (PN) AND at least one of the following diagnostic criteria for NF1:
• Six or more café-au-lait spots (≥ 0.5 cm in prepubertal patients or ≥ 1.5 cm in postpubertal 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


[Note: *Histologic confirmation of tumor not required in the presence of consistent clinical and radiographic findings, but should be considered if malignant degeneration of a PN is clinically suspected.]


• Inoperable PN that has 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 or significant cosmetic problems
• Lesions of the extremity that cause limb hypertrophy or loss of function
• Painful lesions
• Complete resection of a PN with acceptable morbidity is not feasible OR patient refuses surgery
• Measurable PN amenable to volumetric MRI analysis
• Meets one of the following criteria:
• Progressive PN, as defined by one of the following (stratum 1):
• Presence of new PN on MRI or CT scan
• Measurable increase of the PN (≥ 20% increase in the volume, ≥ 13% increase in the product of the two longest perpendicular diameters, or ≥ 6% increase in the longest diameter) on the last two consecutive MRI or CT scans or over a time period of approximately 1 year prior to study entry
• PN without documented radiographic progression (stratum 2)
• No evidence of other cancer requiring treatment with chemotherapy or radiotherapy
• Recovered from all prior therapy
• Prior surgery for progressive PN allowed, provided the PN was incompletely resected and is measurable
• No prior small bowel resection
• No prior treatment with an mTOR inhibitor
• No concurrent chronic treatment with systemic steroids or another immunosuppressive
• Concurrent physiologic or stress doses of steroids allowed in patients with endocrine deficiencies
• No other concurrent investigational or anticancer therapy
• No concurrent live vaccines
• ≥ 3 years of age
• Karnofsky performance status (PS) 50–100% (for patients > 10 years of age); Lansky PS 50–100% (for patients ≤ 10 years of age)
• ANC ≥ 1,500/μL
• Platelet count ≥ 100,000/μL (transfusion independent)
• Hemoglobin ≥ 10.0 g/dL (RBC transfusions allowed)
• Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR creatinine normal based on age
• Bilirubin ≤ 1.5 x upper limit of normal (ULN)
• ALT ≤ 5 x ULN
• Serum albumin ≥ 2 g/dL
• Fasting LDL cholesterol < 160 mg/dL
• No dental braces or prosthesis that interferes with volumetric analysis of the neurofibromas
• No condition that would preclude study participation
• No known history of HIV seropositivity or known immunodeficiency
• Not pregnant or nursing; fertile patients must use effective contraception during and for 3 months after completion of study therapy

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Study Outline:

This is a multicenter study. Patients are stratified according to disease status (radiographically progressive plexiform neurofibromas [stratum 1] vs plexiform neurofibromas without documented radiographic progression [stratum 2]).

Stratum 1:

• Patients receive oral sirolimus twice daily on Days 1–28
• Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity

Stratum 2:

• Patients receive oral sirolimus as in stratum 1
• Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity
• Patients with documented radiographic partial or complete response after completion of 6 courses may receive up to 6 additional courses of sirolimus after documentation of the best radiographic response

• Patients undergo MRI at baseline, after courses 3, 6, 9, and 15, after every 6 courses, and then at the end of treatment for volumetric analysis of their plexiform neurofibromas
• After completion of study therapy, patients are followed periodically for at least 1 month

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Additional Information:

• This trial will be conducted at the NIH Clinical Center in Bethesda, MD. It is open to patients who meet the eligibility requirements, regardless of where they live in the United States.
• There is no charge for medical care received at NIH Clinical Center.
• PDQ (Physicians Data Query) - provides additional details about this study for health care providers.

Reviewed: 6/8/09
Updated: 6/12/08