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Phase I/II Trial Of Repeated Super-selective Intraarterial Cerebral Infusion Of Bevacizumab (Bevacizumab) For Treatment Of Relapsed/Refractory Glioblastoma Multiforme And Anaplastic Astrocytoma.


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Glioblastoma Multiforme, Anaplastic Astrocytoma

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Trial Information

Phase I/II Trial Of Repeated Super-selective Intraarterial Cerebral Infusion Of Bevacizumab (Bevacizumab) For Treatment Of Relapsed/Refractory Glioblastoma Multiforme And Anaplastic Astrocytoma.


1. Non-technical research plan: The current standard of care for recurring GBM is for
patients to receive Bevacizumab (Bevacizumab) intravenously (IV) at 10mg/kg with CPT-11
(Irinotecan) every two weeks until their tumor grows more than 25%. At that point, these
patients are deemed treatment failures and are given another treatment. Because of the
blood brain barrier (BBB) where IV drugs do not penetrate the blood vessel walls well to get
into the brain, no one knows for sure if these IV drugs actually get into the brain after
infusion. The investigators have recently completed a Phase I clinical trial that has shown
that SIACI of Bevacizumab is safe and effective up to a dose of 10mg/kg in patients with
recurrent malignant glioma. This two arm open-label, randomized trial is a follow up study
to that trial and will ask two simple questions: Is it safe to deliver repeated doses
(every three months) of Bevacizumab intra-arterially using these super selective
intra-arterial delivery techniques? Is it necessary to combine this IA regimen of treatment
with biweekly IV Bevacizumab in order to improve progression free survival (PFS) and overall
survival (OS)? Information from this trial will yield important answers to the durability
and efficacy of this delivery technique and may radically change the way chemotherapy is
given to the patients with brain tumors.

Current Standard of Care:

Day 0: Intravenous Bevacizumab (10mg/kg) and CPT-11 Day 14, 28 (and every two weeks
thereafter): Intravenous Bevacizumab and CPT-11

Experimental portion of this proposal: This trial will have two experimental arms that will
be open labeled and non-randomized:

ARM 1:

Day 0: Intraarterial Bevacizumab single dose (15mg/kg) after Mannitol to open the blood
brain barrier Day 28 Intravenous Bevacizumab (10mg/kg) every two weeks thereafter until
disease progression on MRI scan.

If progression occurs, repeat Intraarterial Bevacizumab single dose (15mg/kg) to area of
progression and wait 28 days and then restart Intravenous Bevacizumab (10mg/kg) every two
weeks thereafter until progression on MRI scan.

Repeat Cycle

ARM 2:

Day 0: Intraarterial Bevacizumab single dose (15mg/kg) after Mannitol to open the blood
brain barrier Day 28 No IV Bevacizumab treatment If MRI shows progression then repeat
Intraarterial Bevacizumab single dose (15mg/kg) to area of progression Repeat Cycle

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. The investigators have used this
without complication in the 15 patients from the Phase I protocol as well.

2. To treat patients with one of two arms with repeated intraarterial delivery (SIACI) of
Bevacizumab for patients with recurring or relapsing high grade glioma. Each arm gets
IA delivery with one arm getting IV Bevacizumab biweekly as well and the other arm not
getting intervening IV therapy. In each arm, IA therapy is repeated when MRI shows
progression. Persistent progression after three intra-arterial chemotherapies would
remove the patient from the trial Inclusion criteria: Males or females, 18 years of
age, with documented histologic diagnosis of relapsed or refractory glioblastoma
multiforme (GBM), anaplastic astrocytoma (AA) or anaplastic mixed oligoastrocytoma
(AOA). The lesion must be <3.5cm in greatest diameter and circumscribed to fall within
an area targetable by IA therapy. The patient's KPS > 70 and the patient must have a
life expectancy greater than 12 weeks.

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
serial history, neurological and physical examinations together with MRI will be performed
every cycle or approximately once a month. The following subjects will be taken off
protocol: those with progressive disease after three cycles of IA therapy; those who
experience dose-limiting toxicity (DLT). DLT will be defined as Grade III or worse
non-hematologic and hematologic toxicity or Grade II or worse CNS hemorrhage. Follow-up
will continue until disease progression or death. Survival will be measured from the time of
the first dose of IA Bevacizumab® (given at the start of each treatment cycle).

This treatment may be harmful to a fetus if you were pregnant. If you are a female of
childbearing age, you will be asked to practice birth control methods while participating
in this research study and for 3 months following your treatment. These methods include
oral contraceptives, contraceptive shots, and barrier methods, such as condom use, sponges,
and diaphragms. Fertile males are required to use these barrier methods


Inclusion Criteria:



- 18 years of age or older.

- documented histologic diagnosis of relapsed or refractory glioblastoma multiforme
(GBM), anaplastic astrocytoma (AA) or anaplastic mixed oligoastrocytoma (AOA).

- Circumscribed tumor recurrence with less than 3.5 cm greatest diameter

- Patients with histologically confirmed low-grade brain tumor relapse with an
enhancing tumor on MRI will be evaluated for toxicity only.

- Patients must have at least one confirmed and evaluable tumor site.

- Patients must have a Karnofsky performance status 70% (or the equivalent ECOG level
of 0-2)

- Patients must agree to use a medically effective method of contraception during and
for a period of three months after the treatment period.

Exclusion Criteria:

- Previous treatment with greater than 6 months or 12 cycles of Bevacizumab at 10mg/kg.

- Women who are pregnant or lactating.

- Patients with significant inter-current 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.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Composite overall response rate: The composite overall response rate (CORR) will be examined. The overall response proportion along with a 95% confidence interval will be estimated via binomial proportions.

Outcome Time Frame:

6 months

Safety Issue:

Yes

Principal Investigator

John Boockvar, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Weill Cornell Medical College Department of Neurological Surgery

Authority:

United States: Food and Drug Administration

Study ID:

1001010839

NCT ID:

NCT01269853

Start Date:

October 2010

Completion Date:

October 2015

Related Keywords:

  • Glioblastoma Multiforme
  • Anaplastic Astrocytoma
  • GBM
  • AA
  • AO
  • Brain
  • Tumors
  • Malignant
  • Glioblastoma
  • Multiforme
  • Anaplastic
  • Astrocytoma
  • Astrocytoma
  • Glioblastoma

Name

Location

Weill Cornell Medical College Department of Neurological Surgery 525 East 68th Street STARR 651New York, New York  10065