Trial Of Super-Selective Intraarterial Cerebral Infusion Of Temozolomide (TEMODAR) For Treatment Of Newly Diagnosed Glioblastoma Multiforme And Anaplastic Astrocytoma
|First Received Date ICMJE||August 10, 2010|
|Last Updated Date||December 18, 2012|
|Start Date ICMJE||August 2010|
|Estimated Primary Completion Date||December 2013 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Determine the safety of superselective intra-arterial cerebral infusion of Temozolomide up to a dose of 250 mg/m2 IA. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]|
|Original Primary Outcome Measures ICMJE
||To determine the safety of superselective intra-arterial cerebral infusion of Temozolomide up to a dose of 250mgm2 IA. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]|
|Change History||Complete list of historical versions of study NCT01180816 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Trial Of Super-Selective Intraarterial Cerebral Infusion Of Temozolomide (TEMODAR) For Treatment Of Newly Diagnosed Glioblastoma Multiforme And Anaplastic Astrocytoma|
|Official Title ICMJE||PHASE I TRIAL OF SUPER-SELECTIVE INTRAARTERIAL CEREBRAL INFUSION OF TEMOZOLOMIDE (TEMODAR) FOR TREATMENT OF NEWLY DIAGNOSED 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 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.
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. Inhalation with pentamidine is another option. 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.
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:
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.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 1|
|Study Design ICMJE||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Intervention ICMJE||Drug: Super-Selective Intraarterial Intracranial Infusion of Temozolomide
This phase I clinical research trial will test the hypothesis that temozolomide can be safely used by direct intracranial superselective intraarterial infusion up to a dose of 250mg/m2 to ultimately enhance survival of patients with newly diagnosed GBM/AA.
|Study Arm (s)||Experimental: Temodar
Intervention: Drug: Super-Selective Intraarterial Intracranial Infusion of Temozolomide
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE||30|
|Estimated Completion Date||December 2013|
|Estimated Primary Completion Date||December 2013 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
A. Criteria for Inclusion:
- 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.
|Ages||18 Years and older|
|Accepts Healthy Volunteers||No|
|Location Countries ICMJE||United States|
|NCT Number ICMJE||NCT01180816|
|Other Study ID Numbers ICMJE||0912010814|
|Has Data Monitoring Committee||No|
|Responsible Party||John A. Boockvar, Weill Medical College of Cornell University|
|Study Sponsor ICMJE||Weill Medical College of Cornell University|
|Collaborators ICMJE||Not Provided|
|Investigators ICMJE||Not Provided|
|Information Provided By||Weill Medical College of Cornell University|
|Verification Date||December 2012|
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