Temozolomide and O6-Benzylguanine in Treating Children With Recurrent Brain Tumors
Childhood Central Nervous System Germ Cell Tumor
Childhood Choroid Plexus Tumor
Childhood Grade I Meningioma
Childhood Grade II Meningioma
Childhood Grade III Meningioma
Childhood High-grade Cerebellar Astrocytoma
Childhood High-grade Cerebral Astrocytoma
Childhood Infratentorial Ependymoma
Childhood Low-grade Cerebellar Astrocytoma
Childhood Low-grade Cerebral Astrocytoma
Childhood Mixed Glioma
Childhood Supratentorial Ependymoma
Recurrent Childhood Brain Stem Glioma
Recurrent Childhood Cerebellar Astrocytoma
Recurrent Childhood Cerebral Astrocytoma
Recurrent Childhood Ependymoma
Recurrent Childhood Medulloblastoma
Recurrent Childhood Pineoblastoma
Recurrent Childhood Subependymal Giant Cell Astrocytoma
Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor
Recurrent Childhood Visual Pathway and Hypothalamic Glioma
Other: pharmacological study
Other: laboratory biomarker analysis
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Trial of Temozolomide and O6-Benzylguanine in Pediatric Patients With Recurrent Brain Tumors|
- MTD of temozolomide [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
- Pharmacokinetic parameters [ Time Frame: Baseline and courses 1 and 3 ] [ Designated as safety issue: No ]Summarized using descriptive statistics (mean, standard deviation) if normally distributed. For log-normally distributed data, the geometric mean will be used. If the data are not normally distributed, nonparametric statistics (median, minimum, maximum, interquartile ranges) will be used. Logistic regression models will be used to explore possible relationships between the systemic exposure to temozolomide, O6-benzylguanine, and their respective metabolites and toxicities and antitumor activity.
- Acute toxicities [ Time Frame: 4 weeks (course 1) ] [ Designated as safety issue: Yes ]These toxicities will be tabulated according to dose level.
- Chronic toxicities [ Time Frame: Up to 30 days post-treatment ] [ Designated as safety issue: Yes ]Tabulated according to dose level and course of therapy.
- Histological response [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]Exact confidence interval estimates of traditional response by histologic tumor type will be developed.
- Duration of disease control [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]Kaplan-Meier estimates will also be provided.
- Survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]Kaplan-Meier estimates will also be provided.
|Study Start Date:||October 2002|
|Primary Completion Date:||November 2007 (Final data collection date for primary outcome measure)|
Experimental: Treatment (temozolomide, O6-benzylguanine)
See Detailed Description
Other Name: BGDrug: temozolomide
Other Names:Biological: filgrastim
Given SC or IV
Other Names:Other: pharmacological study
Other Name: pharmacological studiesOther: laboratory biomarker analysis
I. To determine the maximum tolerated dose of temozolomide (Temodar) when administered with O6-benzylguanine (O6-BG) with and without G-CSF support to pediatric patients with refractory brain tumors stratified by previous radiotherapy.
I. To characterize the pharmacokinetics of temozolomide and O6-BG when used in combination.
II. To characterize toxicities associated with the combination of O6-BG and temozolomide with and without G-CSF support.
III. To document antitumor response in patients when treated with O6-BG and temozolomide.
IV. To determine the levels of MGMT enzyme and mismatch repair (MMR) proteins in tumor tissue, investigating a possible correlation with patient outcome.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00052780
|United States, Tennessee|
|Pediatric Brain Tumor Consortium|
|Memphis, Tennessee, United States, 38105|
|Principal Investigator:||Amar Gajjar||Pediatric Brain Tumor Consortium|