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

NCT04283669 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: IRB-300003645W81XWH-17-2-0037
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 15

Brief 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.

Conditions

Neurofibromatosis 2; Progressive Vestibular Schwannoma (VS)

Outcome Measures

Primary Outcomes (1)

• Volumetric Response Rate

  To evaluate efficacy, imaging response is treated as a binary variable whereby patients who achieve a volumetric response (greater than 20% reduction in tumor volume) in the target tumor at any point within 12 months from beginning of therapy are considered responders and all other patients are nonresponders.

  Up to 48 Weeks

Study Arms (1)

Open Label Continuous Treatment

OTHER

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.

Drug: Crizotinib

Interventions

Crizotinib DRUG

Oral

Open Label Continuous Treatment

Eligibility Criteria

• Age: 6 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Alabama at Birmingham: lead
• Memorial Sloan Kettering Cancer Center: collaborator
• Children's Hospital of Philadelphia: collaborator

Study Sites (15)

The University of Alabama at Birmingham (Site 700)

Birmingham, Alabama, 35294, United States

Location

Univ of California @ Los Angeles (Site 325)

Los Angeles, California, 90027, United States

Location

Children's National Medical Center (Site 775)

Washington D.C., District of Columbia, 20010, United States

Location

Children's HealthCare of Atlanta (Site 950)

Atlanta, Georgia, 30324, United States

Location

Lurie Childrens Hospital of Chicago (Site 350)

Chicago, Illinois, 60611, United States

Location

University of Chicago (Site 850)

Chicago, Illinois, 60637, United States

Location

Indiana University (Site 400)

Indianapolis, Indiana, 46202, United States

Location

Johns Hopkins University (Site 250)

Baltimore, Maryland, 21287, United States

Location

Children's Hospital Boston (Site 725)

Boston, Massachusetts, 02115, United States

Location

Washington University - St. Louis (Site 900)

St Louis, Missouri, 63110, United States

Location

New York University Medical Center (Site 200)

New York, New York, 10016, United States

Location

Memorial Sloan Kettering Cancer Center (Site 210)

New York, New York, 10065, United States

Location

Cincinnati Children's Hospital Medical Center (Site 800)

Cincinnati, Ohio, 45229-3039, United States

Location

Children's Hospital of Philadelphia (Site 750)

Philadelphia, Pennsylvania, 19096, United States

Location

Childrens Medical Center - Univ. of Texas SW (Site 917)

Dallas, Texas, 75235, United States

Location

MeSH Terms

Conditions

Neurofibromatosis 2

Interventions

Crizotinib

Condition Hierarchy (Ancestors)

Neuroma, Acoustic; Neurilemmoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neurofibromatoses; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neuroma; Neoplastic Syndromes, Hereditary; Vestibulocochlear Nerve Diseases; Retrocochlear Diseases; Ear Diseases; Otorhinolaryngologic Diseases; Otorhinolaryngologic Neoplasms; Cranial Nerve Neoplasms; Cranial Nerve Diseases; Nervous System Diseases; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Aminopyridines; Pyridines

Results Point of Contact

• Title: Faculty Statistician, Neurofibromatosis Data Coordinating Center
• Organization: Children's Hospital of Philadelphia

liy3@chop.edu

2674253084

Study Officials

• Girish Dhall, MD

  University of Alabama at Birmingham

  STUDY DIRECTOR

• Matthias A Karajannis, MD, MS

  Memorial Sloan Kettering Cancer Center

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chair of of the NFCTC; Protocol PI

Model Details: 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.

Study Record Dates

• First Submitted: February 22, 2020
• First Posted: February 25, 2020
• Study Start: February 18, 2020
• Primary Completion: February 25, 2025
• Study Completion: February 25, 2025
• Last Updated: March 13, 2026
• Results First Posted: March 13, 2026

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (15)