Crizotinib for the Treatment of Neurofibromatosis Type 2 and Progressive Vestibular Schwannoma

Inclusion Criteria

• 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 magnetic resonance imaging (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) ** Note: pre-baseline MRI to be submitted together with baseline MRI for central volumetric review and confirmation of eligibility
• Life expectancy of greater than 1 year
• Lansky/Karnofsky performance status >= 60
• Absolute neutrophil count >= 1,500/ul
• Platelets >= 100,000/ul
• Total bilirubin within =< 1.5 x institutional upper limit of normal
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
• Patients must have a creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 60 ml/min/1.73 m^2 or a normal serum creatinine based on age/gender described below: * Age: Maximum serum creatinine (mg/dL) ** 6 to < 10 years: 1 (male); 1 (female) ** 10 to < 13 years: 1.2 (male); 1.2 (female) ** 13 to < 16 years: 1.5 (male); 1.4 (female) ** >= 16 years: 1.7 (male); 1.4 (female)
• Fully recovered from acute toxic effects of any prior chemotherapy, biological modifiers or radiotherapy
• Any neurologic deficits must be stable for >= 1 week
• Patient or parent/legal guardian must be able to provide signed informed consent and assent (as applicable for minors)

Exclusion Criteria

• Patients currently receiving medical anticancer therapies or who have received medical anticancer therapies within 4 weeks of the start of study drug (including chemotherapy and molecular targeted agents), as these may interfere with the study drug
• Monoclonal antibody treatment and/or agents with prolonged half-lives: At least three half-lives must have elapsed from the last dose prior to enrollment
• Radiation therapy to a study target tumor within 1 year prior to enrollment, or any radiation therapy within 4 weeks prior to enrollment, as these may interfere with our ability to assess response to study drug
• Prior treatment with any investigational drug within the preceding 4 weeks, as they may interfere with the study drug
• Unstable or rapidly progressive disease, including patients who require glucocorticoids for symptomatic control of brain or spinal tumors, as this would represent a high risk for inability to comply with the study requirements
• Use of drugs or foods that are known potent CYP3A4 inhibitors, including but not limited to ketoconazole, itraconazole, miconazole, clarithromycin, erythromycin, ritonavir, indinavir, nelfinavir, saquinavir, amprenavir, delavirdine, nefazodone, diltiazem, verapamil, and grapefruit juice, as this would interfere with study drug metabolism
• Use of drugs that are known potent CYP3A4 inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, tipranavir, ritonavir, and St. John’s wort, as this would interfere with study drug metabolism
• Use of drugs that are CYP3A4 substrates with narrow therapeutic indices, including but not limited to pimozide, aripiprazole, triazolam, dihydroergotamine, ergotamine, astemizole, cisapride, terfenadine and halofantrine, as this would interfere with study drug metabolism
• Ongoing cardiac dysrhythmias of Common Terminology Criteria for Adverse Events (CTCAE) grade >= 2, uncontrolled atrial fibrillation of any grade or prolonged corrected QT (QTc) interval (> 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 diffusion capacity of the lung for carbon monoxide that is 50% of the normal predicted value and/or oxygen (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 jeopardize compliance with study therapy
• Patients unwilling to or unable to comply with the study protocol