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

  • STATUS
    Recruiting
  • End date
    Dec 31, 2025
  • participants needed
    19
  • sponsor
    University of Alabama at Birmingham
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Updated on 19 February 2024
See if I qualify
measurable disease
neutrophil count
crizotinib
cataract
schwartz
multiple meningiomas
nf2 gene
glioma
neurofibroma

Summary

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.

Description

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.

Details
Condition Neurofibromatosis, Neurofibromatosis, Bilateral acoustic neurofibromatosis, Progressive Vestibular Schwannoma (VS)
Age 6-100 years
Treatment Crizotinib
Clinical Study IdentifierNCT04283669
SponsorUniversity of Alabama at Birmingham
Last Modified on19 February 2024

Eligibility

 Yes No Not Sure

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
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/ l
Platelets 100,000/ l
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
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