Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. O6-benzylguanine may increase the effectiveness of temozolomide by making tumor cells more sensitive to the drug.

PURPOSE: Phase I trial to study the safety of combining O6-benzylguanine with temozolomide in treating children who have recurrent or refractory brain tumors.

Further Study Information

OBJECTIVES:

• Determine the maximum tolerated dose of temozolomide when administered with O6-benzylguanine (O^6-BG) with and without filgrastim (G-CSF) in pediatric patients with recurrent brain tumors.

• Describe the toxic effects of this regimen in these patients.

• Characterize the pharmacokinetics of temozolomide and O^6-BG in these patients.

• Investigate the antitumor response of patients treated with temozolomide and O^6-BG.

• Correlate MGMT enzyme and mismatch repair protein levels in tumor tissue with outcome in patients treated with this regimen.

OUTLINE: This is a dose-escalation study of temozolomide with and without filgrastim (G-CSF). Patients are stratified according to prior radiotherapy (RT)/myeloablative therapy (no RT or focal RT vs craniospinal RT or myeloablative therapy).

Patients receive O6-benzylguanine IV continuously on days 1 and 2 and oral temozolomide on day 1. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 2-6 patients in each stratum receive escalating doses of temozolomide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 25% of patients experience DLT. Once the MTD is determined, additional patients are treated at that dose level for a total of 12 patients treated at the MTD.

For courses 1-12, patients experiencing neutropenia may also receive G-CSF subcutaneously or IV daily beginning on day 3 and continuing until blood counts recover.

If neutropenia is the dose-limiting toxicity (DLT) for the first 2 strata, patients are further stratified according to concurrent G-CSF support (yes vs no).Cohorts of 3-6 patients in each stratum receive escalating doses of temozolomide with G-CSF until the MTD is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience DLT. Once the MTD is determined, 6 additional patients are treated at that dose.

Patients are followed for resolution of all adverse events occurring while on treatment and/or within 30 days of the last administration of study drug. Patients will be followed for the shortest of 1) three months after the last protocol based treatment, or 2) the date other therapy is initiated.

PROJECTED ACCRUAL: A maximum of 72 patients (18 per stratum) will be accrued for this study within 3 years.

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed recurrent or refractory brain tumor

• Histological confirmation waived for brain stem gliomas

• Bone marrow involvement by disease allowed

PATIENT CHARACTERISTICS:

Age

• 21 and under

Performance status

• Karnofsky 60-100% OR

• Lansky 60-100%

Life expectancy

• More than 8 weeks

Hematopoietic

• Absolute neutrophil count greater than 1,000/mm^3

• Platelet count greater than 100,000/mm^3*

• Hemoglobin greater than 8 g/dL* NOTE: *Transfusion independent

Hepatic

• Bilirubin normal

• AST and ALT less than 2.5 times normal

• No overt hepatic disease

Renal

• Creatinine no greater than 1.5 times normal OR

• Glomerular filtration rate greater than 70 mL/min

• No overt renal disease

Cardiovascular

• No overt cardiovascular disease

Pulmonary

• No overt pulmonary disease

Other

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• Neurological deficits allowed provided they have been stable for at least 1 week prior to study

• No uncontrolled infection

• No hypersensitivity to dacarbazine, temozolomide, or polyethylene glycol

• No grade 3 or 4 nonhematopoietic toxicity with prior temozolomide

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Recovered from prior biologic therapy

• No more than 2 prior biologic therapy regimens

• At least 6 months since prior bone marrow transplantation

• At least 3 weeks since prior biologic therapy

• More than 2 weeks since prior colony-stimulating factor therapy (e.g., filgrastim [G-CSF], sargramostim [GM-CSF], or epoetin alfa)

Chemotherapy

• Recovered from prior chemotherapy

• No more than 2 prior chemotherapy regimens

• More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas)

• More than 3 months since prior temozolomide

Endocrine therapy

• Concurrent dexamethasone allowed provided dose has been stable for at least 1 week prior to study

Radiotherapy

• At least 3 months since prior craniospinal radiotherapy (at least 18 Gy)

• At least 4 weeks since prior local radiotherapy to the primary tumor

• At least 2 weeks since prior focal irradiation to symptomatic metastatic sites

Surgery

• Not specified

Other

• No other concurrent anticancer or experimental drugs

• Concurrent anticonvulsants allowed

Trial Contact Information

Trial Lead Organizations/Sponsors

Pediatric Brain Tumor Consortium

Amar Gajjar

Study Chair

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00052780
Information obtained from ClinicalTrials.gov on December 14, 2011

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