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Participants must meet the following criteria on screening examination to be |
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eligible to participate in the study |
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Patients must have a confirmed diagnosis of neurofibromatosis 2 by fulfilling |
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National Institute of Health (NIH) criteria or Manchester criteria, or by |
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detection of a causative mutation in the NF2 gene |
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The NIH criteria include presence of |
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Bilateral vestibular schwannomas, OR |
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First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR |
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Two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity |
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The Manchester criteria include presence of |
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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 |
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Unilateral vestibular schwannoma AND any two of: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity, OR |
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Multiple meningiomas (two or more) AND unilateral vestibular schwannoma OR |
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Any two of: schwannoma, glioma, neurofibroma, cataract |
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Patients must have progressive and measurable disease, defined as at least one |
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VS with the following qualities |
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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) |
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MRI evidence of progression over the past 18 months (defined as 20% annualized increase in volume) |
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Age 6 years on day 1 of treatment |
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Life expectancy of greater than 1 year |
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Lansky/Karnofsky performance status 60 |
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Organ and marrow function as defined below |
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Absolute neutrophil count 1,500/ l |
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Platelets 100,000/ l |
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Total bilirubin within 1.5 X institutional upper limit of normal |
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AST (SGOT)/ALT (SGPT) 2.5 X institutional upper limit of normal |
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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 |
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Age: 6 to < 10 years with a Maximum Serum Creatinine (mg/dL) of 1 for Male and 1 for Female |
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Age: 10 to < 13 years with a Maximum Serum Creatinine (mg/dL) of 1.2 for Male and 1.2 for Female |
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Age: 13 to < 16 years with a Maximum Serum Creatinine (mg/dL) of 1.5 for Male and 1.4 for Female |
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Age: 16 years with a Maximum Serum Creatinine (mg/dL) of 1.7 for Male and 1.4 for Female |
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The threshold creatinine values in this Table were derived from the Schwartz |
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formula for estimating GFR utilizing child length and stature data published |
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by the CDC |
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Fully recovered from acute toxic effects of any prior chemotherapy, biological |
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modifiers or radiotherapy |
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Any neurologic deficits must be stable for 1 week |
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Patient or parent/legal guardian must be able to provide signed informed |
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consent and assent (as applicable for minors) |
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Participants who exhibit any of the following conditions at screening will not
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be eligible for admission into the study
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Patients currently receiving medical anticancer therapies or who have received
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medical anticancer therapies within 4 weeks of the start of study drug
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(including chemotherapy and molecular targeted agents), as these may interfere
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with the study drug
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Monoclonal antibody treatment and/or agents with prolonged half-lives: At
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least three half-lives must have elapsed from the last dose prior to
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enrollment
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Radiation therapy to a study target tumor within 1 year prior to enrollment
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or any radiation therapy within 4 weeks prior to enrollment, as these may
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interfere with our ability to assess response to study drug
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Prior treatment with any investigational drug within the preceding 4 weeks, as
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they may interfere with the study drug
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Unstable or rapidly progressive disease, including patients who require
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glucocorticoids for symptomatic control of brain or spinal tumors, as this
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would represent a high risk for inability to comply with the study
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requirements
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Use of drugs or foods that are known potent CYP3A4 inhibitors, including but
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not limited to ketoconazole, itraconazole, miconazole, clarithromycin
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erythromycin, ritonavir, indinavir, nelfinavir, saquinavir, amprenavir
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delavirdine, nefazodone, diltiazem, verapamil, and grapefruit juice, as this
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would interfere with study drug metabolism
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Use of drugs that are known potent CYP3A4 inducers, including but not limited
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to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, tipranavir
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ritonavir, and St. John's wort, as this would interfere with study drug
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metabolism
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Use of drugs that are CYP3A4 substrates with narrow therapeutic indices
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including but not limited to pimozide, aripiprazole, triazolam
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dihydroergotamine, ergotamine, astemizole, cisapride, terfenadine and
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halofantrine, as this would interfere with study drug metabolism
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Ongoing cardiac dysrhythmias of CTCAE grade 2, uncontrolled atrial
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fibrillation of any grade or prolonged QTc interval (>480 msec), as patients
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with these conditions would be expected to have an increased risk for cardiac
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toxicity related to study drug
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Patients who have any severe and/or uncontrolled medical conditions or other
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conditions that could affect their participation in the study such as
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symptomatic congestive heart failure of New York heart Association Class III or IV
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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
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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
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active (acute or chronic) or uncontrolled severe infections liver disease, such as cirrhosis or severe hepatic impairment (Child-Pugh class C)
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Impairment of gastrointestinal function or gastrointestinal disease that may
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significantly alter the absorption of crizotinib (e.g., ulcerative disease
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uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel
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resection)
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Female patients who are pregnant or breast feeding, or adults of reproductive
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potential who are not using effective birth control methods. Adequate
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contraception must be used throughout the trial and for 90 days after the last
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dose of study drug, as the effects of crizotinib on an unborn fetus are not
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known. Females of childbearing potential must have a negative serum pregnancy
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test within 7 days prior to administration of crizotinib
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Male patients whose sexual partner(s) are women of child bearing potential
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who are not willing to use adequate contraception during the study and for 90
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days after the last dose of study drug
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History of significant noncompliance to medical regimens that would jeopardize
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compliance with study therapy
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Patients unwilling to or unable to comply with the study protocol
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