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Super-Selective Intraarterial Cerebral Infusion of Bevacizumab (Avastin) for Treatment of Vestibular Schwannoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01083966
Recruitment Status : Suspended (In the process of transferring IRB to PI's current institution.)
First Posted : March 10, 2010
Last Update Posted : May 17, 2019
Sponsor:
Collaborators:
Feinstein Institute for Medical Research
Hofstra North Shore
Information provided by (Responsible Party):
John Boockvar, MD Zucker SOM @Hofstra/Northwell, Feinstein Institute for Medical Research

Tracking Information
First Submitted Date  ICMJE March 8, 2010
First Posted Date  ICMJE March 10, 2010
Last Update Posted Date May 17, 2019
Study Start Date  ICMJE August 2011
Estimated Primary Completion Date January 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 9, 2010)
Maximum tolerated dose. [ Time Frame: 1 month post procedure ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 9, 2010)
  • Composite overall response rate [ Time Frame: 2 years ]
  • Six-month progression-free survival (PFS) [ Time Frame: 6 months ]
  • Hearing response will be assessed in eligible patients [ Time Frame: 6 months ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Super-Selective Intraarterial Cerebral Infusion of Bevacizumab (Avastin) for Treatment of Vestibular Schwannoma
Official Title  ICMJE Phase I Trial of Super-Selective Intraarterial Cerebral Infusion of Bevacizumab (Avastin) for Treatment of Vestibular Schwannoma (Acoustic Neuroma)
Brief Summary A recent study by Plotkin et al. showed that bevacizumab (Avastin) treatment was followed by clinically meaningful hearing improvement, tumor-volume reduction, or both in some, but not all, patients with Vestibular Schwannoma (VS) who were at risk for complete hearing loss or brain-stem compression from growing VS. Because of the promising results in preliminary studies of Bevacizumab and because of significant experience with the safety of the dosages proposed in this study, this study will offer a safe treatment for patients with VS. Therefore, this phase I clinical research trial will test the hypothesis that Bevacizumab can be safely used by direct intracranial superselective intraarterial infusion up to a dose of 10mg/kg to ultimately enhance survival and hearing function of patients with VS.
Detailed Description

Newer techniques in interventional neuroradiology have allowed for a more selective delivery of catheters higher up into the arterial tree where agents such as chemotherapies, can be delivered without the risk of adverse affects such as blindness. In fact, studies here at Cornell have developed very new and exciting super selective intraarterial delivery treatment for Retinoblastoma and Malignant Glioma brain tumors with little toxicity. Therefore, this trial will ask one simple question: Is it safe to deliver a first dose of Avastin intraarterially using these super selective delivery techniques instead of the standard intravenous route of administration? This should not only increase the amount of drug that gets to the VS but also spare them of any adverse effects from a less selective delivery. During that single dose of intraarterial Avastin, they will also receive a dose of mannitol that opens up the blood brain barrier to improve delivery of the agent to the tumor. After that single dose of Mannitol and Avastin intraarterially, the patient will be evaluated for 4 weeks to assess for toxicity. If no toxicity, then the will go on and get MRI of the brain every two months to assess for response up to 12 months. After this, the subject is done with the "experimental" aspects of the protocol. This is a Phase I trial that is designed to test the safety of the single dose intraarterial delivery of Avastin and Mannitol,.

To summarize:

Current Standard of Care: Surgery or radiosurgery: IV Avastin

Experimental portion of this proposal:

Day 0: Intraarterial Avastin single dose (starting at 2mg/kg and up to 10mg/kg) after Mannitol to open the blood brain barrier Day 28 (and every two months thereafter): MRI brain with contrast

Therefore the experimental aspects of this treatment plan will include:

  1. Subjects will first be treated with Mannitol prior to chemotherapy infusion (Mannitol 25%; 3-10 mL/s for 30seconds) in order to disrupt the blood brain barrier. This technique has been used in several thousand patients in previous studies for the IA delivery of chemotherapy for malignant glioma.
  2. To add a single intraarterial delivery (SIACI) of the Avastin with VS.
  3. The dose escalation algorithm is as follows: We will use a single intracranial superselective intraarterial infusion of Avastin, starting at a dose of 2mg/kg in the first three patients. Assuming no dose limiting toxicity during the first 28 days after IA infusion, an MRI of the brain will be performed. The doses will be escalated to 4,6,8 and finally 10mg/kg in this Phase I trial.

Inclusion criteria Include: Males or females, >=18 years of age, with documented Radiologic or histologic diagnosis of VS

Both hematologic and non-hematologic toxicity will be determined and scored according to the NCI Common Toxicity Criteria (version 3.0). Monitoring will be conducted by post procedure history, neurological and physical examinations together with serial blood counts, prothrombin time (PT), partial thromboplastin time (PTT) and chemistries.

Response will be evaluated after 4 weeks via a MRI with the injection of contrast. The following will be evaluated every cycle, and then during follow-up: neurological examination, physical examination, performance status, laboratory parameters and review of adverse reactions. Contrast enhanced MRI (MRI with gadolinium is the preferable imaging study. The following subjects will be taken off protocol: those with progressive disease; those who experience dose-limiting toxicity (DLT). Follow-up will continue until disease progression or death. Survival will be measured from the time of the first dose of IA Avastin® (given at the start of each treatment cycle).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Vestibular Schwannoma
Intervention  ICMJE Drug: Bevacizumab (Avastin)

Super-Selective Intraarterial Intracranial Infusion of Bevacizumab in Vestibular Schwannoma

This phase I clinical research trial will test the hypothesis that Bevacizumab can be safely used by direct intracranial superselective intraarterial infusion up to a dose of 10mg/kg to ultimately enhance survival and hearing function of patients with VS

Other Name: Avastin
Study Arms  ICMJE Experimental: Avastin
IA Avastin
Intervention: Drug: Bevacizumab (Avastin)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Suspended
Estimated Enrollment  ICMJE
 (submitted: March 9, 2010)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2020
Estimated Primary Completion Date January 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male or female patients of >= 18 years of age.
  • Patients with a documented diagnosis of unilateral or bilateral VS based on MRI and who have evidence of progressive vestibular schwannomas, and are considered poor candidates for surgery and radiation therapy or declined these treatments.
  • Patients must have a Karnofsky performance status >=60% (or the equivalent ECOG level of 0-2) (see Appendix A; Performance Status Evaluation) and an expected survival of >= three months.
  • No chemotherapy for two weeks prior to treatment under this research protocol and no external beam radiation for two weeks prior to treatment under this research protocol.
  • Patients must have adequate hematologic reserve with WBC>=3000/mm3, absolute neutrophils >=1500/mm3 and platelets >=100,000/ mm3. Patients who are on Coumadin must have a platelet count of >=150,000/ mm3.
  • Pre-enrollment chemistry parameters must show: bilirubin< 1.5X the institutional upper limit of normal (IUNL); AST or ALT< 2.5X IUNL and creatinine < 1.5X IUNL.
  • Pre-enrollment coagulation parameters (PT and PTT) must be <1.5X the IUNL.
  • Patients must agree to use a medically effective method of contraception during and for a period of three months after the treatment period. A pregnancy test will be performed on each premenopausal female of childbearing potential immediately prior to entry into the research study.

Exclusion Criteria:

  • Previous treatment with Avastin®.
  • Women who are pregnant or lactating.
  • Women of childbearing potential and fertile men will be informed as to the potential risk of procreation while participating in this research trial and will be advised that they must use effective contraception during and for a period of three months after the treatment period.
  • Patients with significant intercurrent medical or psychiatric conditions that would place them at increased risk or affect their ability to receive or comply with treatment or post-treatment clinical monitoring including MRI with gadolinium.
  • Surgery (including open biopsy), significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgery during study treatment.
  • Current or recent (within 10 days of Avastin) use of aspirin (> 325 mg/day), full dose (i.e., therapeutic dose) of oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes. Prophylactic use of anticoagulants is allowed (e.g., warfarin (1 mg qd) for catheter prophylaxis, and prophylactic low molecular-weight heparin (i.e., enoxaparin [(40mg QD0]).
  • History or evidence of inherited bleeding diathesis or coagulopathy with a risk of bleeding.
  • Inadequately controlled hypertension (blood pressure: systolic > 150 mmHg and/or diastolic > 100 mmHg).
  • Patients with baseline urine dipstick for proteinuria > 2+ must undergo a 24-hours urine collection and must demonstrate ≤ 1 g of protein in 24 hours.
  • Clinically significant (i.e., active) cardiovascular disease (e.g., cerebrovascular accident or myocardial infarction within 6 months prior to randomization),unstable angina, congestive heart failure (NYHA Class ≥ II), or serious cardiac arrhythmia that is uncontrolled by medication or may interfere with administration of study treatment.
  • Serious non-healing sound, active peptic ulcer, or untreated bone fracture.
  • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of enrollment.
  • Known hypersensitivity to Avastin or any of its excipients.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01083966
Other Study ID Numbers  ICMJE 0912010765
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party John Boockvar, MD Zucker SOM @Hofstra/Northwell, Feinstein Institute for Medical Research
Study Sponsor  ICMJE Northwell Health
Collaborators  ICMJE
  • Feinstein Institute for Medical Research
  • Hofstra North Shore
Investigators  ICMJE
Principal Investigator: John Boockvar, MD Feinstein Institute for Medical Research
PRS Account Northwell Health
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP