Phase I Trial of GLIADEL and O(6)-Benzylguanine in Pediatric Patients With Recurrent Malignant Gliomas
3 Years
21 Years
Both
Brain and Central Nervous System Tumors
Trial Information
Phase I Trial of GLIADEL and O(6)-Benzylguanine in Pediatric Patients With Recurrent Malignant Gliomas
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.
Inclusion 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
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
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety Study, Primary Purpose: Treatment
Outcome Measure:
Biologically effective dose of O(6)-benzylguanine administered continuously in pediatric patients with recurrent malignant glioma
Safety Issue:
Yes
Principal Investigator
Ian F. Pollack, MD
Investigator Role:
Study Chair
Investigator Affiliation:
Children's Hospital of Pittsburgh
Authority:
United States: Food and Drug Administration
Study ID:
CDR0000257268
NCT ID:
NCT00045721
Start Date:
March 2003
Completion Date:
July 2004
Related Keywords:
- Brain and Central Nervous System Tumors
- recurrent childhood cerebral astrocytoma
- Nervous System Neoplasms
- Central Nervous System Neoplasms
- Glioma
Name | Location |
|---|---|
| Children's Hospital of Philadelphia | Philadelphia, Pennsylvania 19104 |
| Duke Comprehensive Cancer Center | Durham, North Carolina 27710 |
| Children's National Medical Center | Washington, District of Columbia 20010-2970 |
| Children's Hospital of Pittsburgh | Pittsburgh, Pennsylvania 15213 |
| Children's Hospital and Regional Medical Center - Seattle | Seattle, Washington 98105 |
| Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute | Boston, Massachusetts 02115 |
| St. Jude Children's Research Hospital | Memphis, Tennessee 38105-2794 |
| Texas Children's Cancer Center | Houston, Texas 77030-2399 |
| UCSF Comprehensive Cancer Center | San Francisco, California 94115 |
