Temozolomide & RT Followed by Dose Dense vs Temozolomide & Retinoic Acid in Pts w/Glioblastoma

Study Overview
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Brief Summary
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Patients have a newly diagnosed brain tumor called a malignant glioma and participate in the study to see if it is possible to increase the benefit of temozolomide when given after radiation. A recent study showed that patients with newly diagnosed glioblastoma lived longer when treated with both temozolomide and radiotherapy followed by 6 months of temozolomide than patients treated with radiotherapy alone. Patients will receive standard low dose temozolomide during radiation. After radiation, they will be randomized to receive either more intense temozolomide or continuous low dose temozolomide.

Detailed Description
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This is a randomized phase II study that will test two different adjuvant temozolomide regimens in patients with newly diagnosed glioblastoma multiforme. The goal of this study is to identify a regimen that would be appropriate to bring to a phase III trial and compare to the standard dosing regimen of temozolomide recently reported by Stupp et al. in the New England Journal of Medicine. Secondary goals of this study include: prospective analysis of the prognostic impact of MGMT status and generation of preliminary data regarding this treatment strategy for other types of malignant glioma. The decision regarding which treatment patients receive is made randomly. Neither them or their doctor can select which treatment the patient will receive. There is reason to believe that both of these doses may benefit treating your brain tumor. After 6 months of chemotherapy, and assuming the brain tumor has not shown any sign of growth, they will begin receiving cis-retinoic acid. Cis retinoic acid has been shown in one study to possibly prevent or delay tumor recurrence.

Official Title
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A Randomized Phase II Trial of Concurrent Temozolomide and Radiotherapy Followed by Dose Dense Versus Metronomic Temozolomide and Maintenance Cis-Retinoic Acid for Patients With Newly Diagnosed Glioblastoma and Other Malignant Gliomas

Conditions
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Gliomas, Glioblastoma

Intervention / Treatment
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* Drug: Temozolomide
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologic evidence of a malignant glioma. Tissue block or unstained slides must be available for MGMT analysis. Age 18-70 KPS > 50 Granulocyte count >1.5 X 109/L Platelet count >99 X 109/L SGOT < 2.5X upper limit of normal (ULN). Serum creatinine < 2X ULN. Bilirubin < 2X ULN. All patients must sign written informed consent. Exclusion Criteria: Any prior chemotherapy, radiotherapy and biologic therapy for glioma. Any prior experimental therapy for glioma. Other concurrent active malignancy (with the exception of cervical carcinoma in situ or basal cell ca of the skin). Serious medical or psychiatric illness that would in the opinion of the investigator would interfere with the prescribed treatment. Pregnant or breast feeding women. Refusal to use effective contraception.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metronomic Therapy Cohort<br>Concurrent temozolomide and radiotherapy plus lose dose of temozolomide | Drug: Temozolomide<br>* Focal RT 6000 cGy/ Temozolomide 75 mg/m2 then Temozolomide 50mg/m2 will be given to patients on days 1-28 of each 28 day cycle. Maintenance cis-retinoic acid. This therapy will start at the completion of 6 cycles of adjuvant temozolomide in all patients who have had no clinical or radiographic evidence of tumor progression.Treatment will continue in 28 day cycles until tumor progression.<br>|
| Experimental: Dose-Dense Therapy Cohort<br>Concurrent temozolomide and radiotherapy plus high dose of temozolomide | Drug: Temozolomide<br>* Focal RT 6000 cGy/ Temozolomide 75 mg/m2 plus Temozolomide 150 mg/m2 will be given to patients on days 1-7 and 15-21 of each 28 day cycle. Maintenance cis-retinoic acid. This therapy will start at the completion of 6 cycles of adjuvant temozolomide in all patients who have had no clinical or radiographic evidence of tumor progression.Treatment will continue in 28 day cycles until tumor progression.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 12 Month Overall Survival of Patients With Newly Diagnosed Glioblastoma Multiforme Treated With Concurrent Temozolomide and Radiotherapy Followed by Dose Dense or Metronomic Dosing of Temozolomide and Maintenance Cis-retinoic Acid. |  | until death or date of last follow up, an average of 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival at 6 Months |  | 6 months | 
| Prognostic Impact of Methylated MGMT Status. | MGMT promoter methylation is currently considered the main prognostic biomarker in glioblastoma. Methylation MGMT status will be assessed using real-time PCR. | through study completion, an average of 1 year | 
| To Collect Preliminary Data on the Efficacy of This Regimen and Impact of MGMT Status in Other Malignant Glioma Subtypes. |  | through study completion, an average of 1 year |