| Purpose: |
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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 has consisted
of surgical resection, external beam radiation or both. More recently, a Phase 3 clinical
published by Stupp et al in 2005 showed a benefit for using radiotherapy plus concomitant
and adjuvant Temozolomide. Still, 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 Intra-arterial 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 Temozolomide (Temodar) 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 following the standard 42 day Temozolomide/radiotherapy regimen,
Temozolomide can be safely used by direct intracranial superselective intra-arterial
cerebral infusion (SIACI) up to a dose of 250mg/m2, followed by the standard maintenance
cycle of temozolomide to ultimately enhance survival of patients with newly diagnosed
GBM/AA. The investigators will determine the toxicity profile and maximum tolerated dose
(MTD) of SIACI Temozolomide. The investigators expect that this project will provide
important information regarding the utility of SIACI Temozolomide therapy for malignant
gliomas, and may alter the way these drugs are delivered to our patients in the near future.
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| Study Summary: |
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The current standard of care for newly diagnosed GBM is radiation therapy plus concomitant
oral Temozolomide of doses of 75mg/m2 up to 150mg/m2. Because of the blood brain barrier
(BBB) where drugs do not penetrate the blood vessel walls well to get into the brain, no one
knows for sure if these oral drugs actually get into the brain after infusion. Previous
studies have shown that intra-carotid artery (intra-arterial) delivery is superior to
standard intravenous or oral delivery for increasing the penetration of drug to the brain.
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 into the arterial
tree where chemotherapies can be delivered without the risk of adverse affects such as
blindness. In fact, studies here at WCMC and MSKCC have developed very new and exciting
super selective intra-arterial delivery treatment for Pediatric Eye Tumors with little
toxicity and a clinical trial of intra-arterial delivery of Avastin is currently underway
for GBM. Therefore, this trial will ask one simple question: Is it safe to deliver a dose
of Temozolomide intrarterially using these super selective delivery techniques in addition
to the standard oral route of administration? This should not only increase the amount of
drug that gets to the tumor but also spare the patient many of the adverse effects from a
less selective delivery. Prior to this single dose of intra-arterial Temozolomide, the
patient will also receive a dose of mannitol that will increase the permeability of the
blood brain barrier to improve delivery of the agent to the brain. After this single dose
of mannitol and Temozolomide, the patient will be evaluated for 4 weeks to assess for
toxicity. If there is no toxicity at this point, then the patient will proceed with oral
maintenance Temozolomide chemotherapy. In summary, this is a Phase I trial that is designed
to test the safety of a single dose of intra-arterial delivery of Temozolomide immediately
following 42 days of radiotherapy/oral temozolomide and prior to starting oral maintenance
Temozolomide. : PCP prophylaxis with Bactrim will be provided to subjects on steroid
therapy unless they are allergic to sulfa where alternate form of prophylaxis will be
provided. Dapsone 100 mg orally once daily is usually effective, but methemoglobinemia and
hemolysis in G6PD-deficient individuals can occur.[1] Inhalation with pentamidine is another
option.[2] Similar to treatment of HIV patients, it is administered by aerosol every month
but can cause wheezing from bronchoconstriction. Both agents are less effective than
TMP-SMX, and breakthrough PCP cases have been reported. The third option is atovaquone,
which is given orally, 750-1500 mg daily.[3,4] This agent has been used for treatment of
non-acutely ill patients with PCP, and in recent years has been used for PCP prophylaxis.
Rash has been reported, but usually is well tolerated. Therefore the prophylaxis will vary
on a case to case basis.
To summarize:
Current Standard of Care Therapy:
Days 1-42: Adjuvant dose of Temozolomide 75mg/m2 for 42 days concomitant with focal
radiotherapy Day 42: 4 week rest period Day 70: Maintenance dose of Temozolomide 150mg/m2
once daily for Days 1-5 of a 28 day cycle for 6 cycles
Experimental portion of this proposal:
Days 1-42: Adjuvant dose of Temozolomide 75mg/m2 for 42 days concomitant with focal
radiotherapy Day 42: Single Intra-arterial Mannitol to increase the permeability of the
blood brain barrier followed by Intra-arterial Temozolomide single dose (starting at 75mg/m2
and up to 250mg/m2) followed by 4 week rest period Day 70: Maintenance dose of Temozolomide
150mg/m2 once daily for Days 1-5 of a 28 day cycle for 6 cycles
Therefore the experimental aspects of this treatment plan will include:
1. On day 42, subjects will first be treated with Mannitol prior to chemotherapy infusion
(Mannitol 25%; 3-10 mLs 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. Following the addition of mannitol, the investigators will deliver a single SIACI dose
of Temozolomide for patients with high-grade glioma. After a one-cycle observation
period to assess for toxicity from the IA infusion, the subject will receive the
standard oral maintenance regimen of Temozolomide chemotherapy. The Intra-Arterial
Infusion Procedure will be done under general anesthesia and standard monitoring will
occur.
The dose escalation algorithm is as follows: The investigators will use a single
intracranial superselective intra-arterial infusion of Temozolomide, starting at a dose of
75mg/m2 in the first three patients. Assuming no dose limiting toxicity during the next 28
days after the infusion, the patient will then begin standard maintenance oral Temozolomide
chemotherapy regimen. The doses will be escalated from 75 to 100, to 150, 200, and finally
250mg/m2 in this Phase I trial.
Inclusion criteria Include: Males or females, =>18 years of age, with newly documented
histologic diagnosis of glioblastoma multiforme (GBM), anaplastic astrocytoma (AA) or
anaplastic mixed oligoastrocytoma (AOA).
Both hematologic and non-hematologic toxicity from the IA infusion of Temozolomide will be
determined and scored according to the NCI Common Toxicity Criteria (version 4.02).
Monitoring will also include a MRI of the brain at 4 weeks post infusion.
Most patients with GBM are also monitored every two months with serial history, neurological
and physical examinations together with serial blood counts, prothrombin time (PT), partial
thromboplastin time (PTT) and chemistries. In addition, most patients with GBM have an MRI
performed every two cycles or approximately every two months to assess for tumor
progression. .
Since this is a Phase I trial, response is not a primary endpoint. However, the
investigators will evaluate response to the one time IA Temozolomide therapy with a MRI with
the injection of contrast approximately 4 weeks after infusion. Follow-up of all patients
in the trial after the IA Temozolomide therapy will continue until disease progression or
death. Survival will be measured from the time of the dose of IA Temozolomide®. The
investigators expect patients in the trial to be monitored for 12 months.
This treatment may be harmful to a fetus if you were pregnant. If you are a female of
childbearing potential, you will be asked to practice medically accepted 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.
The patient may be responsible for any additional costs associated with enrollment in the
trial. All costs of the IA delivery and the cost of the drug 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.
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| Criteria: |
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Inclusion Criteria:
A. Criteria for Inclusion:
1. Male or female patients of =>18 years of age.
2. Patients with a newly documented histologic diagnosis of glioblastoma multiforme
(GBM), anaplastic astrocytoma (AA) or anaplastic mixed oligoastrocytoma (AOA).
3. 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.
4. 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.
5. 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.
6. Patients must have adequate hematologic reserve with WBC=>3000mm3, absolute
neutrophils =>1500mm3 and platelets =>100,000 mm3. Patients who are on Coumadin must
have a platelet count of =>150,000 mm3
7. 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.
8. Pre-enrollment coagulation parameters (PT and PTT) must be <=1.5X the IUNL. Patients
taking Coumadin must have an INR less than 2.0.
9. Concomitant Medications:
Growth factor(s): Must not have received within 1 week of entry onto this study.
Steroids: Systemic corticosteroid therapy is permissible in patients with CNS tumors
for treatment of increased intracranial pressure or symptomatic tumor edema. Patients
with CNS tumors who are receiving dexamethasone must be on a stable or decreasing
dose for at least 1 week prior to study entry. We do not believe that study
procedures place subjects with increased intracranial pressure at any additional
risk.
10. Study Specific: Patients on enzyme-inducing anticonvulsants or non-enzyme inducing
anticonvulsants will be allowed in the study. Patients receiving proton pump
inhibitor or H2 blockers will be allowed in the study. Patients taking antacids will
be allowed in the study.
11. Patients who experience dose delays or interruptions in first 42 days of treatment
will still be eligible for the one time dose of SIACI Temozolomide
12. 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.
13. 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.
14. Patients on steroids must receive prophylaxis for PCP pneumonia with Bactrim, unless
they have a history of allergy to sulfa drugs in which case, alternate prophylaxis
will be used.
15. Patients able to understand and give written informed consent and those patients that
are cognitively impaired (which is common in GBM) are eligible for the trial.
Informed consent must be obtained at the time of patient screening (prior to Day 0 of
the procedure) either by the patient or a legalized authorized representative (LAR)
of the patient (healthcare proxy). All subjects must ascent to therapy. If they are
able to understand and provide written informed consent, then consent must be
obtained from the Legally Authorized Representative (LAR)
Exclusion Criteria:
- 1. Women who are pregnant or lactating.
2. 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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