Carmustine Implants and O(6)-Benzylguanine in Treating Children With Recurrent Malignant Glioma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Chemotherapy placed into the surrounding tissue after surgery to remove the tumor may kill any remaining tumor cells. O(6)-benzylguanine may increase the effectiveness of carmustine by making tumor cells more sensitive to the drug. PURPOSE: Phase I trial to study the safety of combining O(6)-benzylguanine with carmustine implants in treating children who have recurrent malignant glioma.

Detailed Description
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OBJECTIVES: Determine the dose of O(6)-benzylguanine that reliably inhibits alkylguanine-DNA alkyltransferase activity in pediatric patients with recurrent malignant glioma. Describe the toxic effects of O(6)-benzylguanine with carmustine implant (Gliadel) in these patients. Investigate antitumor response in patients treated with this regimen. Characterize the pharmacokinetics of O(6)-benzylguanine when administered continuously over a 9-day period. OUTLINE: This is a multicenter, dose-escalation study of O(6)-benzylguanine. Patients receive O(6)-benzylguanine (O6-BG) IV over 1 hour immediately followed by O6-BG IV continuously for 9 days. Two days after initiation of continuous infusion of O6-BG, patients undergo maximal tumor debulking. At the time of surgery, patients receive up to 8 polifeprosan 20 wafers with carmustine (Gliadel) implanted into the resection cavity. Cohorts of up to 14 patients receive escalating doses of continuous infusion O6-BG until the optimally biologically effective dose (BED) is determined. The BED is defined as the dose at which at least 11 of 14 patients meet the target of complete suppression of alkylguanine-DNA alkyltransferase levels. Patients are followed at day 11, at weeks 2, 4, 6, 8, and 12, at months 6, 9, and 12, every 6 months for 4 years, and then annually for 5 years. PROJECTED ACCRUAL: Approximately 20 patients will be accrued for this study within 2 years.

Official Title
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Phase I Trial of GLIADEL and O(6)-Benzylguanine in Pediatric Patients With Recurrent Malignant Gliomas

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Drug: O6-benzylguanine
* Drug: polifeprosan 20 with carmustine implant
* Procedure: adjuvant therapy
* Procedure: conventional surgery
* Procedure: neoadjuvant therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed progressive supratentorial anaplastic astrocytoma or glioblastoma multiforme No multifocal disease or leptomeningeal dissemination of tumor No evidence of tumor crossing midline Limited intraventricular involvement Measurable unilateral mass at least 10 mm by contrast-enhanced MRI Received prior involved-field radiotherapy as a component of prior therapy Amenable to and in need of significant debulking PATIENT CHARACTERISTICS: Age 3 to 21 Performance status Karnofsky 60-100% OR Lansky 60-100% Life expectancy More than 8 weeks Hematopoietic Absolute neutrophil count greater than 1,000/mm3* Platelet count greater than 100,000/mm3* Hemoglobin greater than 8 g/dL (transfusions allowed) NOTE: * Transfusion independent Hepatic Bilirubin no greater than 1.5 times normal AST and ALT less than 3 times normal Albumin at least 2 g/dL No overt hepatic disease Renal Creatinine clearance no greater than 1.5 times normal OR Glomerular filtration rate greater than 70 mL/min No overt renal disease Cardiovascular No overt cardiac disease Pulmonary No overt pulmonary disease Other Neurological deficits must be stable for at least the past week No uncontrolled infection No known hypersensitivity to nitrosoureas or polyethylene glycol Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy At least 6 months since prior bone marrow transplantation More than 2 weeks since prior colony-stimulating growth factors (e.g., filgrastim (G-CSF), sargramostim (GM-CSF), or epoetin alfa) Chemotherapy No more than 2 prior cytotoxic chemotherapy regimens No more than 3 prior chemotherapy regimens total More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas) and recovered Prior systemic carmustine (or other nitrosourea) allowed provided patient did not experience non-hematopoietic grade III/IV toxicity Endocrine therapy Concurrent dexamethasone allowed if on a stable dose for at least the past week Radiotherapy See Disease Characteristics At least 3 months since prior radiotherapy No prior craniospinal irradiation for metastatic disease Surgery See Disease Characteristics Prior biopsy or cytoreductive surgery allowed Other Concurrent anticonvulsants allowed No other concurrent anticancer or investigational drugs

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 21 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


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: O6-benzylguanine|nan|
|Drug: polifeprosan 20 with carmustine implant|nan|
|Procedure: adjuvant therapy|nan|
|Procedure: conventional surgery|nan|
|Procedure: neoadjuvant therapy|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biologically effective dose of O(6)-benzylguanine administered continuously in pediatric patients with recurrent malignant glioma |  |  | 
| Toxicities associated with the administration of O(6)-benzylguanine and carmustine implants. |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor response |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent childhood cerebral astrocytoma