Temozolomide and O6-Benzylguanine in Treating Children With Recurrent Brain Tumors
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|ClinicalTrials.gov Identifier: NCT00052780|
Recruitment Status : Completed
First Posted : January 27, 2003
Last Update Posted : September 30, 2013
|Condition or disease||Intervention/treatment||Phase|
|Childhood Central Nervous System Germ Cell Tumor Childhood Choroid Plexus Tumor Childhood Craniopharyngioma Childhood Ependymoblastoma 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 Medulloepithelioma Childhood Mixed Glioma Childhood Oligodendroglioma 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||Drug: O6-benzylguanine Drug: temozolomide Biological: filgrastim Other: pharmacological study Other: laboratory biomarker analysis||Phase 1|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||72 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I Trial of Temozolomide and O6-Benzylguanine in Pediatric Patients With Recurrent Brain Tumors|
|Study Start Date :||October 2002|
|Actual Primary Completion Date :||November 2007|
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
- MTD of temozolomide [ Time Frame: 28 days ]
- Pharmacokinetic parameters [ Time Frame: Baseline and courses 1 and 3 ]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) ]These toxicities will be tabulated according to dose level.
- Chronic toxicities [ Time Frame: Up to 30 days post-treatment ]Tabulated according to dose level and course of therapy.
- Histological response [ Time Frame: Up to 5 years ]Exact confidence interval estimates of traditional response by histologic tumor type will be developed.
- Duration of disease control [ Time Frame: Up to 5 years ]Kaplan-Meier estimates will also be provided.
- Survival [ Time Frame: Up to 5 years ]Kaplan-Meier estimates will also be provided.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00052780
|United States, Tennessee|
|Pediatric Brain Tumor Consortium|
|Memphis, Tennessee, United States, 38105|
|Principal Investigator:||Amar Gajjar||Pediatric Brain Tumor Consortium|