Phase I Trial of Temozolomide and O6-Benzylguanine in Pediatric Patients With Recurrent Brain Tumors
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
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.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
MTD of temozolomide
Pediatric Brain Tumor Consortium
United States: Food and Drug Administration
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