Subjects with Neurofibromatosis Type 2 (NF2) and progressive vestibular schwannoma (VS) will be treated with crizotinib administered orally. Crizotinib will be taken continuously until disease progression or unacceptable toxicity, in continuous treatment cycles of 28 days each, for a maximum of 12 cycles. Clinical response will be assessed by MRI (volumetrics, primary objective) and audiology at the end of every 3rd cycle. Subjects with volumetric tumor progression will be taken off protocol. Patients who complete 12 cycles of treatment without disease progression, but within the following 24 weeks show subsequent disease progression (defined as \>20% increase in target tumor volume compared to off-treatment volume), will be eligible for re-treatment on study for up to 48 additional weeks, provided they still meet study eligibility criteria.
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 < 10 years with a Maximum Serum Creatinine (mg/dL) of 1 for Male and 1 for
Female
- Age: 10 to < 13 years with a Maximum Serum Creatinine (mg/dL) of 1.2 for Male and 1.2
for Female
- Age: 13 to < 16 years with a Maximum Serum Creatinine (mg/dL) of 1.5 for Male and 1.4
for Female
- Age: ≥ 16 years with a Maximum Serum Creatinine (mg/dL) of 1.7 for Male and 1.4 for
Female
The threshold creatinine values in this Table were derived from the Schwartz formula for
estimating GFR utilizing child length and stature data published by the CDC.
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:
Participants who exhibit any of the following conditions at screening will not be eligible
for admission into the study.
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 CTCAE grade ≥2, uncontrolled atrial fibrillation of any
grade or prolonged 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 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 jeopardize compliance
with study therapy
Patients unwilling to or unable to comply with the study protocol
