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

Alternate Title

Temozolomide and O6-Benzylguanine in Treating Children With Recurrent Brain Tumors

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Completed	21 and under	NCI	PBTC-005 NCT00052780

Objectives

1. Determine the maximum tolerated dose of temozolomide when administered with O6-benzylguanine (O⁶-BG) with and without filgrastim (G-CSF) in pediatric patients with recurrent brain tumors.
2. Determine the toxic effects of this regimen in these patients.
3. Determine the pharmacokinetics of temozolomide and O⁶-BG in these patients.
4. Determine the antitumor response of patients treated with temozolomide and O⁶-BG.
5. Correlate MGMT enzyme and mismatch repair protein levels in tumor tissue with outcome in patients treated with this regimen.

Entry Criteria

Disease Characteristics:

• Histologically confirmed recurrent or refractory brain tumor
  • Histological confirmation waived for brain stem gliomas



• Bone marrow involvement by disease allowed

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

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/mm³
• Platelet count greater than 100,000/mm³*
• 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

Expected Enrollment

A total of 72 patients (18 per stratum) will be accrued for this study within 3 years.

Outcomes

Maximum tolerated dose (MTD) after first 4 weeks of treatment

Best response rate from start of treatment until disease progression/recurrence or three months after completion of study treatment

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). 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).

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, 12 additional patients are treated at that dose.

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.

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 every 3 months for 1 year and then every 6 months for 4 years.

Broniscer A, Gururangan S, MacDonald TJ, et al.: Phase I trial of single-dose temozolomide and continuous administration of o6-benzylguanine in children with brain tumors: a pediatric brain tumor consortium report. Clin Cancer Res 13 (22 Pt 1): 6712-8, 2007.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Pediatric Brain Tumor Consortium

Amar Gajjar, MD, Protocol chair		Ph: 901-595-4599 Email: amar.gajjar@stjude.org

Registry Information
Official Title		Phase I Trial of Temozolomide and O6-Benzylguanine in Pediatric Patients with Recurrent Brain Tumors
Trial Start Date		2002-12-05
Trial Completion Date		2007-11-20
Registered in ClinicalTrials.gov		NCT00052780
Date Submitted to PDQ		2002-10-25
Information Last Verified		2005-08-14
NCI Grant/Contract Number		CA81457