Temozolomide and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme or Anaplastic Astrocytoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Giving chemotherapy together with radiation therapy may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of temozolomide when given together with radiation therapy in treating patients with newly diagnosed glioblastoma multiforme or anaplastic astrocytoma.

Detailed Description
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OBJECTIVES: Primary To determine the maximum tolerated dose of temozolomide when given in combination with hypofractionated intensity-modulated conformal stereotactic radiotherapy in patients with newly diagnosed de novo glioblastoma multiforme or anaplastic astrocytoma. Secondary To determine the time to neuroradiological evidence of tumor recurrence or progression in patients treated with this regimen. To determine the survival time of patients treated with this regimen. To determine the time spent in a Karnofsky performance status of 60-100%. OUTLINE: This is a dose-escalation study of temozolomide. Beginning 1-3 weeks following surgery or biopsy, patients receive oral temozolomide once daily for 5 weeks. Beginning 1 week after starting temozolomide, patients also undergo hypofractionated intensity-modulated conformal stereotactic radiotherapy once daily 5 days a week for 3 weeks. After completion of study treatment, patients are followed at 1 month, 2 months, and 3 months, and then every 3 months thereafter.

Official Title
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A Phase I Trial of Hypofraction Radiotherapy + Temozolomide in the Treatment of Patients With Glioblastoma Multiforme and Anaplastic Astrocytoma of the Brain

Conditions
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Glioblastoma Multiforme/Anaplastic Astrocytoma

Intervention / Treatment
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* Drug: temozolomide
* Radiation: Hypofractionated radiation therapy
* Radiation: Intensity-modulated radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who have De novo glioblastoma multiforme, anaplastic astrocytoma, anaplastic oligodendrogliomas, mixed anaplastic oligoastrocytomas, gliosarcoma of the Brain, not involving the brain stem or optics chiasm, diagnosed following biopsy or tumor removal. Age > 18 years Given written consent Adequate bone marrow reserve(hemoglobin > 10 grams, Absolute neutrophil count > 1500 / mm3, platelets > 100,000/ mm3) Normal renal function(BUN < 24 mg/dL, Creatinine < 1.3 mg/dL) Normal liver function(Total Bilirubin < 1.5 mg/dL, SGPT/ALT < 60 U/L) Exclusion Criteria: Have a Karnofsky score of < 60 [Appendix B] or age < 18 years. Prior chemotherapy and/or radiotherapy of their glioblastomamultiforme, anaplastic astrocytoma, anaplastic oligodendrogliomas, mixed anaplastic oligoastrocytomas, gliosarcoma. Tumors located in the brainstem or optic chiasm. Prior radiation therapy to the brain Prior chemotherapy within the past 6 weeks.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hypofractionation Radiotherapy+Temozolomide<br>Patients will receive temozolomide PO daily for 5 weeks. Beginning week 1 after initiation of temozolomide therapy, patients undergo HIMRT times a week for a total of 15 fractions. | Drug: temozolomide<br>* Chemotherapy will be given for 5 weeks; it will start 1 week before Radiotherapy, will continue for the 3 weeks of Radiotherapy, and will continue for 1 week post-Radiotherapy. Dose Level 1: 50 mg/m2 x first 4 weeks/75 mg/m2 x last 1 weeks of treatment Dose Level 2: 65 mg/m2 x first 4 weeks/75 mg/m2 x last 1 weeks of treatment Dose Level 3: 75 mg/m2 over the entire 5 weeks of treatment<br>* Other names: Temodal;Radiation: Hypofractionated radiation therapy<br>* Patients will undergo HIMRT<br>Radiation: Intensity-modulated radiation therapy<br>* Patients undergo HIMRT<br>* Other names: IMRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose(MTD)of Temozolomide(TMZ) | This study is designed as a phase I dose escalation trial using the Standard Method of dose escalation of three patients per dose level to determine the MTD of TMZ (up to 75 mg/m 2 /day) when TMZ is used with HIMRT for patients with glioblastoma multiforme(GBM) or Anaplastic Astrocytoma(AA)of the brain. The 3 dose levels will be evaluated using the standard method to determine if either represents an MTD based on DLT. If DLT is not observed at all doses level, the greater of the three levels will be recommended for phase II evaluations of treatment effect. | up to 12-16 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Neuroradiological Evidence of Tumor Recurrence or Progression | As a small phase I study, no inferential statistical tests of hypotheses are planned. Data collected will be providing descriptive summary statistics. However, these estimates will allow statistically sound experimental designs and sample size calculations for subsequent studies of therapeutic effect. | up to 12-16 months | 
| Survival Time | All patients will be followed to death. Active follow-up with disease evaluation with scans will be terminated if the patient's physician deems it in the patient's interest not to continue or upon patient request. | up to 2 years | 
| Time Spent in a Karnofsky Performance Status of 60-100% | Time spent in a KPS ≥70 was calculated from the date of diagnosis of Karonofsky Performance Status decline (KPS<70) or censored at the last date the patient was known with KPS ≥70. The KPS higher scores indicates normal activity status. | up to 12-16 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GBM/AA, adult giant cell glioblastoma, adult gliosarcoma, adult anaplastic astrocytoma, adult glioblastoma