Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01180816 |
| Other study ID # |
14-292A |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
August 2010 |
| Est. completion date |
August 11, 2020 |
Study information
| Verified date |
March 2021 |
| Source |
Northwell Health |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
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 central nervous system (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.
Description:
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.
Therefore, this trial will ask one simple question: Is it safe to deliver a dose of
Temozolomide intraarterially 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.
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
intraarterial (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.
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.
