Arsenic Trioxide, Temozolomide, and Radiation Therapy in Treating Patients With Malignant Glioma That Has Been Removed By Surgery

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as arsenic trioxide and 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. Giving arsenic trioxide and temozolomide together with radiation therapy after surgery may kill any remaining tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of arsenic trioxide and temozolomide when given together with radiation therapy and to see how well they work in treating patients with malignant glioma that has been removed by surgery.

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose (MTD) of arsenic trioxide and temozolomide when combined with radiotherapy in patients with resected supratentorial malignant glioma. (Phase I) Determine the toxicity of this regimen in these patients. (Phase I) Secondary Determine the 6- and 12-month progression-free survival of patients treated with this regimen once an MTD is reached. (Phase II) Determine the radiographic response for patients treated with the above regimen. (Phase II) Determine the safety of this regimen in these patients. (Phase II) OUTLINE: This is a phase I, dose-escalation study of arsenic trioxide and temozolomide followed by a phase II study. Phase I: Patients undergo radiotherapy once daily 5 days a week and receive oral temozolomide once daily for approximately 6½ weeks. Patients also receive arsenic trioxide IV over 1-4 hours once daily, 5 days a week in week 1 and then twice a week in weeks 2-7. Beginning within 3-5 weeks after completion of radiotherapy, patients receive oral temozolomide once daily on days 1-5. Treatment with temozolomide repeats every 28 days for up to 1 year in the absence of disease progression and unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of arsenic trioxide and temozolomide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 1 of 3 or 2 of 6 patients experience dose-limiting toxicity. Phase II: Patients undergo radiotherapy and receive arsenic trioxide and temozolomide as in phase I at the MTD. Patients then receive temozolomide as in phase I for up to 1 year in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for 1 year. PROJECTED ACCRUAL: A total of 12-18 patients will be accrued for the phase I portion of this study. A total of 25 patients will be accrued for the phase II portion of this study.

Official Title
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A Phase I/II Trial of Arsenic Trioxide and Temozolomide in Combination With Radiation Therapy for Patients With Malignant Gliomas

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Drug: arsenic trioxide
* Drug: temozolomide
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed supratentorial malignant glioma of 1 of the following types: Glioblastoma multiforme Gliosarcoma Anaplastic astrocytoma Anaplastic oligodendroglioma Anaplastic mixed gliomas Anaplastic gliomas not otherwise specified Has undergone surgical resection of tumor Patients with biopsy only are eligible Evaluable or measurable disease following resection of recurrent tumor is not mandated for entry into the study No brain metastases PATIENT CHARACTERISTICS: Karnofsky performance status 60-100% Life expectancy > 3 months WBC > 3,000/mm^3 Absolute neutrophil count > 2,000/mm^3 Platelet count > 100,000/mm^3 Hemoglobin > 10 g/dL (eligibility level for hemoglobin may be reached by transfusion) Creatinine ≤ 1.5 mg/dL Bilirubin ≤ 2 mg/dL Transaminases ≤ 2 times the upper limit of normal Serum potassium* > 4.0 mEq/dL Serum magnesium* > 1.8 mg/dL NOTE: *If these serum electrolytes are below the specified limits on the baseline laboratory tests, supplemental electrolytes should be administered to bring the serum concentrations to these levels before administering arsenic trioxide Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after completion of study treatment No second-degree heart block QT interval ≤ 460 msec No other malignancy within the past 3 years except curatively treated carcinoma in situ or basal cell carcinoma of the skin Patients who cannot undergo MRI are not eligible for this study No other serious concurrent infection or other medical illness that would jeopardize the ability of the patient to receive the therapy in this protocol with reasonable safety PRIOR CONCURRENT THERAPY: See Disease Characteristics Patients must have recovered from the effects of surgery prior to the start of treatment (10-14 days minimum) and be maintained on a stable corticosteroid regimen for 5 days Concurrent glucocorticoid therapy allowed at the smallest effective dose Patients must be on non-enzyme-inducing anti-convulsants to minimize any drug reaction No prior radiation therapy, chemotherapy, immunotherapy, therapy with biologic agents (including immunotoxins, immunoconjugates, antisense agents, peptide receptor antagonists, interferons, interleukins, tumor-infiltrating lymphocytes, lymphokine-activated killer cells, or gene therapy), or hormonal therapy for their brain tumor

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: Radiation + temozolomide and arsenic trioxide<br>Radiation therapy followed by the combination of temozolomide and arsenic trioxide at the maximum tolerated dose determined in phase 1 | Drug: arsenic trioxide<br>* Arsenic trioxide administered intravenously at a dose of 0.20mg/kg Daily x 5 week then twice per week<br>* Other names: TRISENOX;Drug: temozolomide<br>* Temozolomide administered orally once per day 1 hour prior to radiation therapy at a dose of 75 mg/m2 x 42 days; at a dose of 200mg/m2 for 5 days every cycle (1 cycle = 28 days) after radiation therapy<br>* Other names: Temodar;Radiation: radiation therapy<br>* All patients will receive 5940-6120 cGy of radiation therapy as 28-33 treatments/fractions (180-200 cGy/treatment) depending on whether they receive standard 3-D conformal radiation therapy or intensity modulated radiation therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of arsenic trioxide and temozolomide in combination with radiotherapy | Escalating doses of study drug until dose limiting toxicities are observed. | Toxicity evaluated prior to each treatment cycle | 
| Collect data on the toxicity of arsenic and temozolomide during radiation therapy | Toxicity of this drug combination during radiation therapy will be assessed. | Toxicity evaluated prior to each treatment cycle | 
| Assess serum biomarkers and correlate with tumor tissue | Blood will be drawn at baseline, during radiation therapy, and prior to each cycle of chemotherapy to assess serum biomarkers and correlate with tumor tissue. | At baseline, during radiation therapy, and prior to each cycle of chemotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine progression free survival at 6 and 12 months | Patients will undergo an MRI and neurological evaluation every 6 months while on chemotherapy. | At 6 and 12 months after beginning chemotherapy | 
| Determine time to disease progression | Disease status will be assessed by MRI and neurological examination every 6 months until disease progression. | At 6 and 12 months after beginning chemotherapy | 
| To determine overall survival | Survival status will be evaluated every 6 months while on treatment. | Every 6 months while on treatment | 
| To determine radiographic response to study regimen | Radiographic response will be assessed by MRI every 6 months while on treatment | Every 6 months while on treatment | 
| To collect safety data during the radiation therapy phase | EKG's will be done once per week and labs twice per week during radiation therapy phase to evaluate safety data. | Weekly during radiation therapy | 
| To evaluate a potential surrogate marker for outcomes | Blood will be drawn to analyze methylation patterns as a surrogate marker for outcomes at baseline, before and after radiation therapy, and every 2 cycles during chemotherapy. | At baseline, before and after radiation therapy, and every 2 cycles during chemotherapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult mixed glioma, adult anaplastic astrocytoma, adult gliosarcoma, adult anaplastic oligodendroglioma, adult glioblastoma, adult giant cell glioblastoma, recurrent adult brain tumor