| Conditions: |
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Vestibular Schwannoma |
| Purpose: |
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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.
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| Study Summary: |
|
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).
|
| Criteria: |
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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.
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| NCT ID: |
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NCT01083966 |
| Primary Contact: |
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Principal Investigator
John Boockvar, MD
Weill Medical College of Cornell University
John Boockvar, MD
Phone: 212-746-1996
Email: jab2029@med.cornell.edu
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| Backup Contact: |
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Email: taw2015@med.cornell.edu
Tamika Wong, MPH
Phone: 212-746-1788
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| Location Contact: |
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New York, New York 10065
United States
There is no listed contact information for this specific location.
Site Status: Recruiting |