Phase 2 Study of Bevacizumab in Children and Young Adults With Neurofibromatosis 2 and Progressive Vestibular Schwannomas (NF-2)

This study is currently recruiting participants.
Verified May 2013 by University of Alabama at Birmingham
Sponsor:
Collaborator:
Genentech
Information provided by (Responsible Party):
University of Alabama at Birmingham
ClinicalTrials.gov Identifier:
NCT01767792
First received: January 7, 2013
Last updated: January 31, 2014
Last verified: May 2013
  Purpose

To determine the hearing response rate at 24 weeks after treatment with bevacizumab for symptomatic vestibular schwannomas (VS) in children and young adults with NF2.


Condition Intervention Phase
Neurofibromatosis Type 2
Progressive Vestibular Schwannomas
Drug: Bevacizumab
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Open-label, Phase 2 Study of Bevacizumab in Children and Young Adults With Neurofibromatosis 2 and Progressive Vestibular Schwannomas That Are Poor Candidates for Standard Treatment With Surgery or Radiation

Resource links provided by NLM:


Further study details as provided by University of Alabama at Birmingham:

Primary Outcome Measures:
  • Hearing Response Rates [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    To determine the hearing response rate at 24 weeks after treatment with bevacizumab for symptomatic vestibular schwannomas (VS) in children and young adults with NF2.


Secondary Outcome Measures:
  • safety [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    The secondary objectives are: (1) to determine the safety and tolerability of bevacizumab in this patient population; (2) to determine the radiographic response rate (defined as an decrease in VS volume by ≥ 20% compared to baseline) during bevacizumab treatment; (3) to determine the durability of hearing response, as measured by freedom from hearing loss from the time of hearing response (defined as a decrease in word recognition score below the upper limit of the 95% critical difference of the baseline word recognition score; (4) to determine the durability of radiographic response, as measured from the time of first response to tumor progression (defined as an increase in volume of > 20% compared to lowest tumor volume during treatment) (5) to determine changes in function of the auditory system during bevacizumab treatment; (6) to explore changes in tinnitus during treatment.

  • tolerability [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    The secondary objectives are: (1) to determine the safety and tolerability of bevacizumab in this patient population; (2) to determine the radiographic response rate (defined as an decrease in VS volume by ≥ 20% compared to baseline) during bevacizumab treatment; (3) to determine the durability of hearing response, as measured by freedom from hearing loss from the time of hearing response (defined as a decrease in word recognition score below the upper limit of the 95% critical difference of the baseline word recognition score;(4) to determine the durability of radiographic response, as measured from the time of first response to tumor progression (defined as an increase in volume of > 20% compared to lowest tumor volume during treatment) (5) to determine changes in function of the auditory system during bevacizumab treatment; (6) to explore changes in tinnitus during treatment.

  • durability [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    The secondary objectives are: (1) to determine the safety and tolerability of bevacizumab in this patient population; (2) to determine the radiographic response rate (defined as an decrease in VS volume by ≥ 20% compared to baseline) during bevacizumab treatment; (3) to determine the durability of hearing response, as measured by freedom from hearing loss from the time of hearing response (defined as a decrease in word recognition score below the upper limit of the 95% critical difference of the baseline word recognition score; (4) to determine the durability of radiographic response, as measured from the time of first response to tumor progression (defined as an increase in volume of > 20% compared to lowest tumor volume during treatment) (5) to determine changes in function of the auditory system during bevacizumab treatment; (6) to explore changes in tinnitus during treatment.

  • Radiographic Response [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    The secondary objectives are: (1) to determine the safety and tolerability of bevacizumab in this patient population; (2) to determine the radiographic response rate (defined as an decrease in VS volume by ≥ 20% compared to baseline) during bevacizumab treatment; (3) to determine the durability of hearing response, as measured by freedom from hearing loss from the time of hearing response (defined as a decrease in word recognition score below the upper limit of the 95% critical difference of the baseline word recognition score; (4) to determine the durability of radiographic response, as measured from the time of first response to tumor progression (defined as an increase in volume of > 20% compared to lowest tumor volume during treatment) (5) to determine changes in function of the auditory system during bevacizumab treatment; (6) to explore changes in tinnitus during treatment.

  • Changes in function of auditory system [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    The secondary objectives are: (1) to determine the safety and tolerability of bevacizumab in this patient population; (2) to determine the radiographic response rate (defined as an decrease in VS volume by ≥ 20% compared to baseline) during bevacizumab treatment; (3) to determine the durability of hearing response, as measured by freedom from hearing loss from the time of hearing response (defined as a decrease in word recognition score below the upper limit of the 95% critical difference of the baseline word recognition score; (4) to determine the durability of radiographic response, as measured from the time of first response to tumor progression (defined as an increase in volume of > 20% compared to lowest tumor volume during treatment) (5) to determine changes in function of the auditory system during bevacizumab treatment; (6) to explore changes in tinnitus during treatment.

  • Changes in Tinnitus during treatment [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    The secondary objectives are: (1) to determine the safety and tolerability of bevacizumab in this patient population; (2) to determine the radiographic response rate (defined as an decrease in VS volume by ≥ 20% compared to baseline) during bevacizumab treatment; (3) to determine the durability of hearing response, as measured by freedom from hearing loss from the time of hearing response (defined as a decrease in word recognition score below the upper limit of the 95% critical difference of the baseline word recognition score; (4) to determine the durability of radiographic response, as measured from the time of first response to tumor progression (defined as an increase in volume of > 20% compared to lowest tumor volume during treatment) (5) to determine changes in function of the auditory system during bevacizumab treatment; (6) to explore changes in tinnitus during treatment.


Estimated Enrollment: 24
Study Start Date: May 2013
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Bevacizumab
Follow participant for 2 years and assess hearing response rates
Drug: Bevacizumab

Treatment will be administered on an outpatient basis. Bevacizumab is administered by IV infusion at a dose of 10 mg/kg every 2 weeks for 24 weeks (induction therapy, see Schema). One cycle lasts 28 days and includes two infusions of bevacizumab. Clinical response will be assessed by audiology and MRI at weeks 12 and 24. Subjects with hearing decline at weeks 12 and 24 will be taken off of protocol. After week 24, patients with a clinical response or stable disease (together comprising "clinical benefit") will transition to maintenance therapy with bevacizumab.

During the maintenance phase, subjects will be treated with open-label bevacizumab 5 mg/kg every 3 weeks for up to 72 weeks. Subjects will be followed with audiology and MRI scans every 12 weeks. The total time of the study will be 96 weeks (24 weeks induction + 72 weeks maintenance).

Other Names:
  • rhuMAb
  • VEGF
  • Avastin®

Detailed Description:

Subjects will be treated with open-label bevacizumab 10 mg/kg every 2 weeks for 24 weeks (induction therapy). Clinical response will be assessed by audiology and MRI at weeks 12 and 24. Subjects with hearing decline at weeks 12 or 24 will be taken off of protocol. At week 24, patients with a clinical response or stable disease (together comprising "clinical benefit") will transition to maintenance therapy with bevacizumab. During the maintenance phase, subjects will be treated with open-label bevacizumab 5 mg/kg every 3 weeks for up to 72 weeks. Subjects will be followed with audiology and MRI scans every 12 weeks. The total time of the study will be 96 weeks (24 weeks induction + 72 weeks maintenance).

Subjects will be allowed to increase their bevacizumab dose to 10 mg/kg every 2 weeks during maintenance therapy if they experience hearing decline during maintenance therapy (defined as decrease in word recognition score below the 95% critical difference compared with the word recognition score at baseline, Appendix A). Subjects will be taken off of study if their word recognition score does not remain within the 95% critical difference after receiving bevacizumab 10 mg/kg every 2 weeks.

  Eligibility

Ages Eligible for Study:   12 Years to 30 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  • Patients must have measurable disease, defined as at least one VS > 1.0 ml (on volumetric analysis) that can be accurately measured by contrast-enhanced cranial MRI scan with fine cuts through the internal auditory canal (3 mm slices, no skip).
  • Age 12 to 30 years on day 1 of treatment. Given the potential risk of long-term bevacizumab use, children under age 12 are not eligible for treatment. Adults older than 30 are not eligible as these patients may be eligible for other bevacizumab-based protocols.
  • Life expectancy of greater than 1 year.
  • Karnofsky performance status ≥ 70.
  • Participants must have normal organ and marrow function as defined below:
  • Leukocytes > 3,000/mcL
  • Absolute neutrophil count > 1,500/mcL
  • Platelets > 100,000/mcL
  • Total bilirubin within normal institutional limits
  • 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 m2 or a normal serum creatinine based on age described in the table below:
  • Age (years) Maximum Serum Creatinine (mg/dL) 12<age≤15 1.2 >15 1.5
  • Subjects must have a target VS with the following qualities:
  • Not amenable to surgery due to patient refusal, high risk for surgical complications (e.g., damage to lower cranial nerve function, tumor size > 3 cm in longest diameter, or multilobulated tumor appearance on MRI scan).
  • Associated with a word recognition score of < 85%
  • Documented clinical progression defined as EITHER:
  • Progressive hearing loss (defined as a decline in word recognition score below the 95% critical difference interval from baseline score [Appendix A] related to VS (i.e., not due to prior interventions such as surgery or radiation)

OR

  • Progressive tumor growth in the preceding 18 months, defined as ≥ 20% increase in volume
  • The effects of bevacizumab on the developing human fetus are unknown. For this reason and because bevacizumab agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
  • Ability to understand and the willingness to sign written informed consent and assent documents.
  • Must have established relationship with primary care physician and provide contact information

Exclusion Criteria:

  • Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study.
  • Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Prior radiation treatment to the target vestibular schwannoma is allowed if provided 3 years prior to participation in the clinical trial. Prior radiation treatment to non-target tumors is allowed.
  • Participants may not be receiving any other study agents.
  • Patients with nervous system tumors associated with NF2 (e.g., schwannomas, meningiomas, ependymomas, or gliomas) will not be excluded from this clinical trial unless (in the opinion of the investigator) these tumors are growing and are likely to require treatment during the clinical trial.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to bevacizumab.
  • Patients with known hypersensitivity of Chinese hamster ovary cell products, other recombinant human antibodies, or compounds of similar chemical or biologic composition to bevacizumab.
  • Inability to tolerate periodic MRI scans or gadolinium contrast.
  • Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements.
  • History of arterial/myocardial disease.
  • Clinically significant cardiovascular disease, such as:
  • Inadequately controlled HTN (for adults: SBP > 160 mmHg and/or DBP > 90 mmHg despite antihypertensive medication; for children: please refer to Appendix D for age-appropriate values indicating ≥ Grade 2)
  • History of CVA within 12 months
  • Myocardial infarction or unstable angina within 12 months
  • New York heart association grade II or greater congestive heart failure
  • Serious and inadequately controlled cardiac arrhythmia
  • Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection)
  • Clinically significant peripheral vascular disease
  • Pregnant women are excluded from this study because bevacizumab is an anti-angiogenic agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with bevacizumab, breastfeeding should be discontinued if the mother is treated with bevacizumab. These potential risks may also apply to other agents used in this study.
  • HIV-positive patients or cancer survivors are eligible for this study if they fulfill all other eligibility criteria.
  • Concurrent use of anti-coagulant drugs (not including prophylactic doses), history of coagulopathy, or evidence of bleeding diathesis or coagulopathy.
  • Imaging (CT or MRI) evidence of hemorrhage deemed significant by the treating physician (> grade 1). Subjects with history of CNS hemorrhage are not eligible.
  • Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC) ratio. For UPC ratio > 0.5, 24-hour urine protein should be obtained and the level should be <1000 mg for patient enrollment.
  • Serious or non-healing wound, ulcer or bone fracture.
  • History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to day 1.
  • Invasive procedures defined as follows:
  • Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1 therapy
  • Brain biopsy within 28 days prior to day 1 of therapy (wounds must be fully healed from brain biopsies performed more than 28 days prior to day 1 of therapy)
  • Anticipation of need for major surgical procedures during the course of the study
  • Core biopsy within 7 days prior to D1 therapy
  • Prior treatment with bevacizumab.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01767792

Contacts
Contact: Bruce R Korf, MD, PhD 205.934.9411 bkorf@uab.edu
Contact: Karen A Cole-Plourde, BS 205.934.5140 kcole@uab.edu

Locations
United States, California
Children's Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Tena Rosser, MD    323-361-2471    trosser@chla.usc.edu   
Sub-Investigator: Marco Giovannini, MD         
Sub-Investigator: Carrie Bearden, PhD         
United States, District of Columbia
Children's National Medical Center Recruiting
Washington, District of Columbia, United States, 20010
Contact: Roger Packer, MD    202-476-2120    rpacker@cnmc.org   
Sub-Investigator: Jaishri Blakeley, MD         
United States, Illinois
University of Chicago Recruiting
Chicago, Illinois, United States, 60637
Contact: James Tonsgard, MD    773-702-6488    tonsgard@midway.uchicago.edu   
Contact: Cynthia MacKenzie, RN, BSN    773.702.6487    cmackenzie@peds.bsd.uchicago.edu   
Sub-Investigator: Stewart Goldman, MD         
Sub-Investigator: Robert Listernick, MD         
United States, Indiana
Indiana Unversity Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Wade Clapp, MD    317-278-9290    kcole@uab.edu   
Contact: Kent Robertson, MD    317-274-0991    krobert@iupui.edu   
United States, Maryland
National Cancer Institute (NCI) Not yet recruiting
Bethesda, Maryland, United States, 20892
Contact: Brigitte Widemann, MD    301-496-7387    widemannb@mail.nih.gov   
Contact: Andy Gillespie, RN    301.402.1848    gillesan@mail.nih.gov   
United States, Massachusetts
Children' Hospital Boston and Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Nicole Ullrich, MD    617-355-3193    nicole.ullrich@childrens.harvard.edu   
Sub-Investigator: Scott Plotkin, MD         
Sub-Investigator: Mark Kieran, MD         
United States, Missouri
Washington University - St. Louis Recruiting
St. Louis, Missouri, United States, 63110
Contact: David Gutmann, MD    314-362-7379    gutmann@neuro.wustl.edu   
Contact: Lisa Murray    314.454.4240    'Murray_KW@kids.wustl.edu   
Principal Investigator: David Gutmann, MD         
United States, New York
New York University Medical Center Recruiting
New York, New York, United States, 10016
Contact: Jeffrey C Allen, MD    212-263-9907    jeffrey.allen@nyumc.org   
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229-4006
Contact: Elizabeth Schorry, MD    513-636-9863    elizabeth.schorry@cchmc.org   
Principal Investigator: Elizabeth Schorry, MD         
Sub-Investigator: Brad Welling, MD         
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19096
Contact: Michael Fisher, MD    215-590-2800    fisherm@email.chop.edu   
Contact: Ratnakar Patti    267.426.5503    pattir@email.chop.edu   
United States, Utah
University of Utah Recruiting
Salt Lake City, Utah, United States, 84132
Contact: Dave Viskochil, MD    801-581-8943    dave.viskochil@hsc.utah.edu   
Contact: Heather Hanson    801.587.7689    Heather.Hanson@hsc.utah.edu   
Sponsors and Collaborators
University of Alabama at Birmingham
Genentech
Investigators
Study Chair: Scott Plotkin, MD Massachusetts General Hospital
  More Information

No publications provided

Responsible Party: University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT01767792     History of Changes
Other Study ID Numbers: AVF4807, W81XWH-12-1-0155
Study First Received: January 7, 2013
Last Updated: January 31, 2014
Health Authority: United States: Food and Drug Administration
United States: Data Safety and Monitoring Board
United States: Medical Monitor
United States: Department of Defense External Advisory Board
United States: External Review Committee

Keywords provided by University of Alabama at Birmingham:
Neurofibromatosis Type 2
Progressive Vestibular Schwannomas

Additional relevant MeSH terms:
Neurofibromatosis 2
Neurilemmoma
Neurofibromatoses
Neurofibromatosis 1
Osteitis Fibrosa Cystica
Neuroma, Acoustic
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Nerve Sheath Neoplasms
Neoplasms, Nerve Tissue
Neuroma
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Nervous System Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Neurofibroma
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Bone Diseases, Endocrine
Bone Diseases
Musculoskeletal Diseases
Neoplasms by Site
Vestibulocochlear Nerve Diseases

ClinicalTrials.gov processed this record on April 17, 2014