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

This study is currently recruiting participants.
Verified December 2012 by Weill Medical College of Cornell University
Sponsor:
Information provided by (Responsible Party):
John A. Boockvar, Weill Medical College of Cornell University
ClinicalTrials.gov Identifier:
NCT01269853
First received: December 22, 2010
Last updated: December 18, 2012
Last verified: December 2012

December 22, 2010
December 18, 2012
October 2010
October 2014   (final data collection date for primary 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. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • Six-month progression-free survival PFS will be measured from the date of the first dose of SIACI Bevacizumab to the date of progression. OS will be measured from the date of the first dose of SIACI Bevacizumab to the date of death. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
Same as current
Complete list of historical versions of study NCT01269853 on ClinicalTrials.gov Archive Site
The safety of repeated SIACI of mannitol and Bevacizumab at 15mg/kg. The descriptive frequency of subjects experiencing toxicities will also be tabulated. [ Time Frame: 1 month ] [ Designated as safety issue: Yes ]
Same as current
Not Provided
Not Provided
 
Trial Of Repeated Super-selective Intraarterial Cerebral Infusion Of Bevacizumab (Bevacizumab) For Treatment Of Relapsed/Refractory Glioblastoma Multiforme And Anaplastic Astrocytoma.
Phase I/II Trial Of Repeated Super-selective Intraarterial Cerebral Infusion Of Bevacizumab (Bevacizumab) For Treatment Of Relapsed/Refractory Glioblastoma Multiforme And Anaplastic Astrocytoma.

The high-grade malignant brain tumors, glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA), comprise the majority of all primary brain tumors in adults. This group of tumors also exhibits the most aggressive behavior, resulting in median overall survival durations of only 9-12 months for GBM, and 3-4 years for AA. Initial therapy consists of either surgical resection, external beam radiation or both. All patients experience a recurrence after first-line therapy, so improvements in both first-line and salvage therapy are critical to enhancing quality-of-life and prolonging survival. It is unknown if currently used intravenous (IV) therapies even cross the blood brain barrier (BBB). The investigators have shown in a previous phase I trial that a single Superselective Intraarterial Cerebral Infusion (SIACI) of Bevacizumab (up to 15mg/kg) is safe and effective in the treatment of recurrent GBM. Therefore, this phase I/II clinical research trial is an extension of that trial in that the investigators seek to test the hypothesis that repeated dosing of intra-arterial Bevacizumab is safe and effective in the treatment of recurrent malignant glioma. By achieving the aims of this study the investigators will also determine if IV therapy with Bevacizumab should be combined with repeated selected intra-arterial Bevacizumab to improve progression free and overall survival. The investigators expect that this project will provide important information regarding the utility of repeated SIACI Bevacizumab therapy for malignant glioma, and may alter the way these drugs are delivered to the patients in the near future.

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

Interventional
Phase 1
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Glioblastoma Multiforme
  • Anaplastic Astrocytoma
  • Drug: Bevacizumab
    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
  • Drug: Bevacizumab

    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

  • Experimental: Arm 2
    Intervention: Drug: Bevacizumab
  • Experimental: Arm 1
    Intervention: Drug: Bevacizumab
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
100
October 2015
October 2014   (final data collection date for primary outcome measure)

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.
Both
18 Years and older
No
Contact: John Boockvar, MD 212-746-1996 jab2029@med.cornell.edu
Contact: Trisha Ali-Shaw 212-746-7373 tra2002@med.cornell.edu
United States
 
NCT01269853
1001010839
No
John A. Boockvar, Weill Medical College of Cornell University
Weill Medical College of Cornell University
Not Provided
Principal Investigator: John Boockvar, MD Weill Cornell Medical College Department of Neurological Surgery
Weill Medical College of Cornell University
December 2012

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