Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Completed	3 to 21	NCI	PBTC-009 NCT00045721

Objectives

1. Determine the dose of O(6)-benzylguanine that reliably inhibits alkylguanine-DNA alkyltransferase activity in pediatric patients with recurrent malignant glioma.
2. Determine the toxic effects of O(6)-benzylguanine and polifeprosan 20 with carmustine implant (Gliadel) in these patients.
3. Determine antitumor response in patients treated with this regimen.

Entry Criteria

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

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

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

Expected Enrollment

Approximately 20 patients will be accrued for this study within 2 years.

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.

Trial Contact Information

Trial Lead Organizations

Pediatric Brain Tumor Consortium

Ian Pollack, MD, Protocol chair		Ph: 412-692-5881

Registry Information
Official Title		Phase I Trial of GLIADEL and O(6)-Benzylguanine in Pediatric Patients with Recurrent Malignant Gliomas
Trial Start Date		2003-03-03
Registered in ClinicalTrials.gov		NCT00045721
Date Submitted to PDQ		2002-07-11
Information Last Verified		2004-07-19
NCI Grant/Contract Number		U01-CA81457