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


Phase 1
3 Years
21 Years
Not Enrolling
Both
Brain and Central Nervous System Tumors

Thank you

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 PhiladelphiaPhiladelphia, Pennsylvania  19104
Duke Comprehensive Cancer CenterDurham, North Carolina  27710
Children's National Medical CenterWashington, District of Columbia  20010-2970
Children's Hospital of PittsburghPittsburgh, Pennsylvania  15213
Children's Hospital and Regional Medical Center - SeattleSeattle, Washington  98105
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer InstituteBoston, Massachusetts  02115
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
Texas Children's Cancer CenterHouston, Texas  77030-2399
UCSF Comprehensive Cancer CenterSan Francisco, California  94115