Phase 2 Clinical Trial of Crizotinib for Children and Adults With Neurofibromatosis Type 2 and Progressive Vestibular Schwannomas

Inclusion Criteria

Participants must meet the following criteria on screening examination to be eligible to participate in the study:

Patients must have a confirmed diagnosis of neurofibromatosis 2 by fulfilling National Institute of Health (NIH) criteria or Manchester criteria, or by detection of a causative mutation in the NF2 gene.

The NIH criteria include presence of:

• Bilateral vestibular schwannomas, OR
• First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR
• Two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity.

The Manchester criteria include presence of:

• Bilateral vestibular schwannomas, OR First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR - Two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity OR
• Unilateral vestibular schwannoma AND any two of: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity, OR
• Multiple meningiomas (two or more) AND unilateral vestibular schwannoma OR
• Any two of: schwannoma, glioma, neurofibroma, cataract.

Patients must have progressive and measurable disease, defined as at least one VS with the following qualities:

• ≥ 0.75 ml (on volumetric analysis) that can be accurately measured by contrast-enhanced cranial MRI scan with fine cuts through the internal auditory canal (1 mm slices, no skip)
• MRI evidence of progression over the past 18 months (defined as ≥20% annualized increase in volume)

Age ≥ 6 years on day 1 of treatment.

Life expectancy of greater than 1 year.

Lansky/Karnofsky performance status ≥ 60

Organ and marrow function as defined below:

• Absolute neutrophil count ≥ 1,500/ μl
• Platelets ≥ 100,000/ μl
• Total bilirubin within ≤ 1.5 X institutional upper limit of normal
• AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal
• Patients must have a creatinine clearance or radioisotope GFR ≥60ml/min/1.73 ≥60ml/min/1.73 m2 or a normal serum creatinine based on age/gender described in the table below:
• Age: 6 to 480 msec), as patients with these conditions would be expected to have an increased risk for cardiac toxicity related to study drug

Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

• symptomatic congestive heart failure of New York heart Association Class III or IV
• unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
• severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or O2 saturation that is 90% or less at rest on room air
• active (acute or chronic) or uncontrolled severe infections liver disease, such as cirrhosis or severe hepatic impairment (Child-Pugh class C)

Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of crizotinib (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)

Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. Adequate contraception must be used throughout the trial and for 90 days after the last dose of study drug, as the effects of crizotinib on an unborn fetus are not known. Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to administration of crizotinib.

Male patients whose sexual partner(s) are women of child bearing potential, who are not willing to use adequate contraception during the study and for 90 days after the last dose of study drug.

History of significant noncompliance to medical regimens that would jeopardiz