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Study Title: Phase I Trial of Temozolomide and O6-Benzylguanine in Pediatric Patients with Recurrent Brain Tumors
Description:
Stratum 1 will accrue relapsed patients who have been treated with focal radiation therapy and patients who have not received radiation therapy. Stratum 2 will accrue patients who have had prior craniospinal irradiation or myeloblative therapy. If neutropenia is the dose limiting toxicity in either strata, as anticipated by the adult phase I study, additional patients will be accrued allowing the use of G-CSF to establish whether higher doses of temozolomide can be administered with this form of hematological support.
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Stratification Scheme |
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Stratum 1 |
Stratum 2 |
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No prior RT or prior focal RT only |
Prior craniospinal radiation (³18 Gy) or myeloablative therapy |
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Stratum 1a |
Stratum 1b* |
Stratum 2a |
Stratum 2b* |
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No G-CSF used |
G-CSF used |
No G-CSF use |
G-CSF used |
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*Strata 1b and/or 2b will open only if the MTD for the ‘a’ stratum includes neutropenia |
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O6-BG will be administered intravenously over 1 hour at a dose of 120mg/m2, followed immediately by O6-BG 30 mg/m2/day for 48 hours. Temozolomide will be administered orally, in a fasting state, no sooner than 6 hours after the end of the one hour bolus infusion of O6-BG. Temozolomide dosing will begin at 267 mg/m2. The temozolomide dose will be increased in approximately 33% increments in subsequent cohorts until the MTD is reached.
Objectives:
Primary:
Secondary:
To characterize the pharmacokinetics of temozolomide and O6-BG when used in combination.
To characterize toxicities associated with the combination of O6-BG and temozolomide with and without G-CSF support.
To document antitumor response in patients when treated with O6-BG and temozolomide.
To determine the levels of MGMT enzyme and mismatch repair (MMR) proteins in tumor tissue, investigating a possible correlation with patient outcome.
Rationale:
The combination of O6-BG and temozolomide should increase the therapeutic index of temozolomide based on in vitro and in vivo data with the combination of O6-BG and nitrosoureas. However, the optimal schedule for using O6-BG and temozolomide in combination is unknown. Important factors that determine the dose and schedule of O6-BG are the amount of drug required to maximally deplete the MGMT in the tumor tissue and the time required for regeneration of MGMT in the tumor tissue.
Eligibility Criteria:
Recurrent or refractory pediatric brain tumors. A histopathologic diagnosis from either the initial presentation or at the time of recurrence is required for all but brain stem gliomas.
Performance status: Karnofsky or Lansky >= 60%; Life expectancy > 8 weeks.
Neurological Deficits: Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to study entry.
Chemotherapy: No more than 2 previous chemotherapy/biologic therapy regimens. Evidence of recovery from prior chemotherapy/biologic therapy. No myelosuppressive chemotherapy within 3 weeks (6 weeks if a nitrosourea agent) of study entry. Patients who have received temozolomide are eligible if they have not received the drug in the past 3 months and did not experience any non–hematopoietic Grade 3/4 toxicity with prior temozolomide therapy.
XRT: >= 3 months prior to study entry for craniospinal irradiation (>= 18 Gy); >= 4 weeks for local radiation to primary tumor; and >= 2 weeks prior to study entry for focal irradiation to symptomatic metastatic sites.
Bone Marrow Transplant: >= 6 months prior to study entry.
Anti-convulsants: Patients will be eligible for this study even if they are receiving anti-convulsants.
Growth factors: Off all colony forming growth factor(s) > 2 weeks prior to study entry (G-CSF, GM-CSF, Erythropoietin).
Dexamethasone: Patients who are receiving dexamethasone must be on a stable dose for at least 1 week prior to study entry.
Contact:
| Study Chair | Study Co-Chair |
Amar J. Gajjar, MD |
Friedman, Henry, MD |
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