Clinical Trial: Bevacizumab for Symptomatic Vestibular Schwannoma in Neurofibromatosis Type 2 (NF2)

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Phase 2 Study of Bevacizumab in Children and Adults With Neurofibromatosis Type 2 and Symptomatic Vestibular Schwannoma

Brief Summary: People who have neurofibromatosis type 2 (NF2) can have tumors that grow on the auditory nerves and cause hearing loss. These tumors are called vestibular schwannomas (VSs), or acoustic neuromas. People with NF2 can also get schwannomas in other parts of their body, as well as tumors called meningiomas and ependymomas. Because VSs can cause hearing loss, many people with NF2 will have treatment to preserve their hearing. This treatment usually involves surgery. Because surgery has risks and is not able to help everyone with VSs, other methods of treatment are being explored. One area of exploration is looking to see if there is a drug that can be taken that might prevent the VSs from growing larger and causing hearing loss or brainstem compression. This study is exploring whether a drug that is approved by the FDA and is currently used to treat other tumors might also work to treat VSs. Based on people who have taken this drug to treat VSs already, there is some reason to think that it might be helpful to certain people with NF2. People enrolled in this study will receive the drug one time every three weeks for one year by infusion. This study will follow subjects over the course of the year that the person is taking the drug and for six months after the drug is stopped. This study is recruiting people who have NF2 and are currently having symptoms of tinnitus, dizziness, and/or hearing loss from their VSs. If you have NF2 and are currently having symptoms caused by your VSs, you may be eligible to participate.

Detailed Summary:

PRIMARY OBJECTIVES:

I. The primary objective of this study is to determine the activity of bevacizumab for treatment of symptomatic vestibular schwannomas (VS) defined as progressive hearing loss in patients with neurofibromatosis type 2 (NF2) based on objective hearing response.

SECONDARY OJBECTIVES:

I. Determine the safety and tolerability of bevacizumab in this patient population on an every three week dosing schedule of 7.5mg/kg for 12 months of therapy.

II. Assess the rate of radiographic response (>= 20% reduction in volume). III. Determine the growth rate of VS using volumetric MRI analysis in comparison to 1-dimensional and 2-dimensional measurements.

IV. Assess changes in function of the auditory system during bevacizumab treatment.

V. Assess the vascular permeability (Ktrans), relative cerebral blood volume/flow, mean transit time, and mean vessel diameter from perfusion-weighted MRI.

VI. Assess the change in circulating endothelial cells, circulating progenitor cells, and plasma angiogenic proteins in subjects receiving bevacizumab treatment.

VII. Observe the impact of bevacizumab on non-VS tumors in patients with NF2 via whole body MRI.

VIII. Explore hearing related QOL measures throughout treatment. IX. Explore the effect of treatment with bevacizumab on vestibular function (to be evaluated at NCI only).

OUTLINE:

Patients receive bevacizumab intravenously (IV) over
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome: Change in hearing response, defined as increased word recognition score above the 95% critical threshold that is maintained across two sequential evaluation time points [ Time Frame: Baseline to 3 months ]

Original Primary Outcome: Hearing response

Current Secondary Outcome:

• Incidence of serious or life threatening toxicities [ Time Frame: Up to 6 months post-treatment ]
  The proportion of patients with serious or life threatening toxicities will be estimated along with 95% confidence intervals.
• Rate of radiographic response, defined by the change in tumor volume compared to baseline (>= 20% reduction in volume) [ Time Frame: Baseline to 6 months post-treatment ]
  The proportion of radiographic response will be estimated using binomial distribution. The duration of the response will be summarized as mean and confidence interval of the mean.
• Growth rate of VS using volumetric MRI [ Time Frame: 18 months ]
  The rate of change over 12 months will be estimated using generalized linear model.
• Changes in function of the auditory system [ Time Frame: Baseline to 6 months post-treatment ]
  The primary DPOAE measurement will be treated non-parametrically (present or absent across time) DPOAE's will be considered present at the frequency of F2 when the distortion product is 6dB above the noise floor. Variables will be analyzed for differences using t-tests if the effects and sample sizes warrant, but this may not be advisable given the small numbers to be accrued.
• Change in vascular permeability (Ktrans), relative cerebral blood volume/flow, mean transit time, and mean vessel diameter from perfusion-weighted MRI [ Time Frame: Baseline to week 72 ]
  The correlations between imaging parameters and hearing response will then be estimated based on the estimated changes. Generalized Estimating Equations (GEE) will be used to estimate association of imaging parameters in hearing responses after treatment. The greatest on-treatment change from the pretreatment baseline value during the course of the study will be computed for each subject. Statistical comparisons between MRI parameters measured on different study time point will be performed with a two-tailed paired exact Wilcoxon test.
• Quality of the life, assessed using Health Survey Short Form-36 (SF-36), Speech and Spatial Qualities questionnaire (SSQ), and Tinnitus Reaction Questionnaire (TRQ) [ Time Frame: Baseline ]
  Standard scoring manuals will be used to summarize the each item or domains. A overall score at each time point will be compared with the baseline score two-tailed pared t-test will be used to assess the change form the baseline and MANOVA could be used to assess the association between the quality of life and the change of the hearing score. Each item or domain will be summarized using descriptive statistics. Comparisons of on-treatment and post-treatment values with the pre-treatment baseline value will be performed using paired t-tests.
• Quality of the life, assessed using SF-36, SSQ, andTRQ [ Time Frame: 6 months ]
  Standard scoring manuals will be used to summarize the each item or domains. A overall score at each time point will be compared with the baseline score two-tailed pared t-test will be used to assess the change form the baseline and MANOVA could be used to assess the association between the quality of life and the change of the hearing score. Each item or domain will be summarized using descriptive statistics. Comparisons of on-treatment and post-treatment values with the pre-treatment baseline value will be performed using paired t-tests.
• Quality of the life, assessed using SF-36, SSQ, andTRQ [ Time Frame: 12 months ]
  Standard scoring manuals will be used to summarize the each item or domains. A overall score at each time point will be compared with the baseline score two-tailed pared t-test will be used to assess the change form the baseline and MANOVA could be used to assess the association between the quality of life and the change of the hearing score. Each item or domain will be summarized using descriptive statistics. Comparisons of on-treatment and post-treatment values with the pre-treatment baseline value will be performed using paired t-tests.
• Quality of the life, assessed using SF-36, SSQ, andTRQ [ Time Frame: 18 months ]
  Standard scoring manuals will be used to summarize the each item or domains. A overall score at each time point will be compared with the baseline score two-tailed pared t-test will be used to assess the change form the baseline and MANOVA could be used to assess the association between the quality of life and the change of the hearing score. Each item or domain will be summarized using descriptive statistics. Comparisons of on-treatment and post-treatment values with the pre-treatment baseline value will be performed using paired t-tests.

Original Secondary Outcome:

• Radiographic response
• Vascular permeability
• Plasma biomarkers
• Quality of life

Dates:
Date Received: September 1, 2010
Date Started: October 2010
Date Completion:
Last Updated: December 27, 2016
Last Verified: December 2016