Super-Selective Intraarterial Intracranial Infusion of Avastin (Bevacizumab)
| Status: | Completed |
|---|---|
| Conditions: | Brain Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/13/2015 |
| Start Date: | July 2009 |
| End Date: | January 2015 |
| Contact: | John Boockvar, MD |
| Email: | jab2029@nyp.org |
| Phone: | 212-746-1996 |
Phase I Trial of Super-Selective Intraarterial Intracranial Infusion of Avastin (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).
Superselective Intraarterial Cerebral Infusion (SIACI) is a technique that can effectively
increase the concentration of drug delivered to the brain while sparing the body of systemic
side effects. One currently used drug called, Bevacizumab (Avastin) has been shown to be
active in human brain tumors but its actual CNS penetration is unknown. 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 of patients with relapsed/refractory GBM/AA. By achieving the
aims of this study we will determine the toxicity profile and maximum tolerated dose (MTD of
SIACI Bevacizumab. We expect that this project will provide important information regarding
the utility of SIACI Bevacizumab therapy for malignant glioma, and may alter the way these
drugs are delivered to our patients in the near future.
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).
Superselective Intraarterial Cerebral Infusion (SIACI) is a technique that can effectively
increase the concentration of drug delivered to the brain while sparing the body of systemic
side effects. One currently used drug called, Bevacizumab (Avastin) has been shown to be
active in human brain tumors but its actual CNS penetration is unknown. 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 of patients with relapsed/refractory GBM/AA. By achieving the
aims of this study we will determine the toxicity profile and maximum tolerated dose (MTD of
SIACI Bevacizumab. We expect that this project will provide important information regarding
the utility of SIACI Bevacizumab therapy for malignant glioma, and may alter the way these
drugs are delivered to our patients in the near future.
The current standard of care for recurring GBM is for patients to receive Bevacizumab
(Avastin) 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. Previous studies have shown that if you
want to increase your penetration of drug to the brain, that intra-carotid artery
(intraarterial) delivery is superior to standard intravenous delivery. Previous techniques
using intra arterial (intracarotid) infusion still were non-selective as drug delivery still
went to all blood vessels in the brain, so patients still had significant adverse events,
such as blindness. 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 and MSKCC have developed very new and exciting super selective
intraarterial delivery treatment for Pediatric Eye Tumors with little toxicity. Therefore,
this trial will ask one simple question: Is it safe to delivery a patient's 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 tumor but also spare the patient any adverse effects from a less
selective delivery. During that single dose of intraarterial Avastin, the patient will also
receive a dose of mannitol that opens up the blood brain barrier to improve delivery of the
agent to the brain. 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
patient will go on and get the standard chemotherapy (Avastin and CPT-11) every two weeks as
is routine unless they fail. After this you are 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, prior to starting standard IV Avastin and
CPT-11.
In summary:
Current Standard of Care:
Day 0: Intravenous Avastin (10mg/kg) and CPT-11 Day 14, 28 (and every two weeks thereafter):
Intravenous Avastin and CPT-11
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 weeks thereafter):
Intravenous Avastin and CPT-11
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 prior to beginning the
standard IV Avastin and CPT-11 therapy for patients with recurring or relapsing high
grade glioma. After a one cycle observation period assess for toxicity from the IA
infusion, the subject will receive Intravenous (IV) bevacizumab 10 mg/kg and irinotecan
(CPT-11) 125mg/m2 every 14 days as is standard therapy for relapsing recurring GBM.
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, the patient will then begin their standard chemotherapy regimen which is Avastin
and CPT-11 every two weeks. 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 histologic
diagnosis of relapsed or refractory glioblastoma multiforme (GBM), anaplastic astrocytoma
(AA) or anaplastic mixed oligoastrocytoma (AOA).
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
CT scan (at 6-12 hours post procedure), serial history, neurological and physical
examinations together with serial blood counts, prothrombin time (PT), partial
thromboplastin time (PTT) and chemistries. MRI will be performed every two cycles or
approximately every two months.
Response will be evaluated after two cycles of chemotherapy via a MRI with the injection of
contrast. Subjects who show an objective response (reduction in tumor size) or stable
disease after 2 cycles of treatment will be able to continue on study. Progressive disease
will require that subjects be taken off the research protocol. 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 except in case
where MRI is contraindicated i.e., in those with pacemakers or metallic implants. In these
subjects, CT with contrast is acceptable) will be performed every two-treatment cycles under
this research protocol. 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).
The patient will not be responsible for any additional costs associated with enrollment in
the trial. All costs of the IA delivery will be submitted to the patient's insurance
provider. WCMC will not be named as a sponsor of the study nor will it cover the cost of the
experimental procedure.
(Avastin) 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. Previous studies have shown that if you
want to increase your penetration of drug to the brain, that intra-carotid artery
(intraarterial) delivery is superior to standard intravenous delivery. Previous techniques
using intra arterial (intracarotid) infusion still were non-selective as drug delivery still
went to all blood vessels in the brain, so patients still had significant adverse events,
such as blindness. 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 and MSKCC have developed very new and exciting super selective
intraarterial delivery treatment for Pediatric Eye Tumors with little toxicity. Therefore,
this trial will ask one simple question: Is it safe to delivery a patient's 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 tumor but also spare the patient any adverse effects from a less
selective delivery. During that single dose of intraarterial Avastin, the patient will also
receive a dose of mannitol that opens up the blood brain barrier to improve delivery of the
agent to the brain. 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
patient will go on and get the standard chemotherapy (Avastin and CPT-11) every two weeks as
is routine unless they fail. After this you are 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, prior to starting standard IV Avastin and
CPT-11.
In summary:
Current Standard of Care:
Day 0: Intravenous Avastin (10mg/kg) and CPT-11 Day 14, 28 (and every two weeks thereafter):
Intravenous Avastin and CPT-11
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 weeks thereafter):
Intravenous Avastin and CPT-11
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 prior to beginning the
standard IV Avastin and CPT-11 therapy for patients with recurring or relapsing high
grade glioma. After a one cycle observation period assess for toxicity from the IA
infusion, the subject will receive Intravenous (IV) bevacizumab 10 mg/kg and irinotecan
(CPT-11) 125mg/m2 every 14 days as is standard therapy for relapsing recurring GBM.
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, the patient will then begin their standard chemotherapy regimen which is Avastin
and CPT-11 every two weeks. 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 histologic
diagnosis of relapsed or refractory glioblastoma multiforme (GBM), anaplastic astrocytoma
(AA) or anaplastic mixed oligoastrocytoma (AOA).
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
CT scan (at 6-12 hours post procedure), serial history, neurological and physical
examinations together with serial blood counts, prothrombin time (PT), partial
thromboplastin time (PTT) and chemistries. MRI will be performed every two cycles or
approximately every two months.
Response will be evaluated after two cycles of chemotherapy via a MRI with the injection of
contrast. Subjects who show an objective response (reduction in tumor size) or stable
disease after 2 cycles of treatment will be able to continue on study. Progressive disease
will require that subjects be taken off the research protocol. 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 except in case
where MRI is contraindicated i.e., in those with pacemakers or metallic implants. In these
subjects, CT with contrast is acceptable) will be performed every two-treatment cycles under
this research protocol. 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).
The patient will not be responsible for any additional costs associated with enrollment in
the trial. All costs of the IA delivery will be submitted to the patient's insurance
provider. WCMC will not be named as a sponsor of the study nor will it cover the cost of the
experimental procedure.
INCLUSION
- Male or female patients of greater or equal18 years of age.
- Patients with a documented histologic diagnosis of relapsed or refractory
glioblastoma multiforme (GBM), anaplastic astrocytoma (AA)
- Patients with a histologically confirmed low-grade brain tumor who relapse with an
enhancing tumor on MRI can be evaluated for toxicity only.
- Patients must have at least one confirmed and evaluable tumor site.
*A confirmed tumor site is one in which is biopsy-proven. NOTE: Radiographic
procedures (e.g., Gd-enhanced MRI or CT scans) documenting existing lesions must have
been performed within three weeks of treatment on this research study.
- Patients must have a Karnofsky performance status greater or equal to 60% (or the
equivalent ECOG level of 0-2) (see Appendix A; Performance Status Evaluation) and an
expected survival of greater or equal to three months.
- Patients must be able to understand informed consent. Informed consent must be
obtained at the time of patient screening.
- Because of known concerns with Avastin and wound healing, all craniotomy patients are
eligible for the treatment if they have had a craniotomy > two weeks prior to IA
therapy. Craniotomy after SIACI bevacizumab therapy should wait 4 weeks.
- Pre-enrollment coagulation parameters (PT and PTT) must be less than or equal to1.5X
the IUNL.
- Patients must have adequate hematologic reserve with WBC greater than or equal to
2800/mm3, absolute neutrophils greater than or equal to1500/mm3 and platelets greater
than or equal to 100,000/ 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.
- No external beam radiation for four weeks prior to treatment under this research
protocol.
- No chemotherapy for three weeks prior to treatment under this research protocol.
EXCLUSION:
- Patients previously treated with more than 6 cycles (28 days each) of Bevacizumab at
10/mg/kg.
- Women who are pregnant or lactating.
- Women of childbearing potential and fertile men who decline to 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.
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