Clinical trial NCT00045721: Carmustine Implants and O(6)-Benzylguanine in Treating Children With Recurrent Malignant Glioma
Official title: Phase I Trial of GLIADEL and O(6)-Benzylguanine in Pediatric Patients With Recurrent Malignant Gliomas
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Brain and Central Nervous System Tumors
Keywords: recurrent childhood cerebral astrocytoma
Lead sponsor: Pediatric Brain Tumor Consortium
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-01-27
Enrollment: 3
Sex: ALL
Minimum age (years): 3
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility 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

Primary outcomes:
measure: Biologically effective dose of O(6)-benzylguanine administered continuously in pediatric patients with recurrent malignant glioma
measure: Toxicities associated with the administration of O(6)-benzylguanine and carmustine implants.
Secondary outcomes:
measure: Tumor response
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Comprehensive Cancer Center
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
state: Massachusetts
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Cancer Center
state: Texas
city: Seattle
country: United States
facility: Children's Hospital and Regional Medical Center - Seattle
state: Washington
Study officials:
affiliation: University of Pittsburgh
name: Ian F. Pollack, MD
role: STUDY_CHAIR
References: