PBTC-005 Abstract for Health Professionals  

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.

Stratification Scheme

Stratum 1

Stratum 2

No prior RT or prior focal RT only

Prior craniospinal radiation (³18 Gy) or myeloablative therapy

Stratum 1a

Stratum 1b*

Stratum 2a

Stratum 2b*

No G-CSF used

G-CSF used

No G-CSF use

G-CSF used

*Strata 1b and/or 2b will open only if the MTD for the ‘a’ stratum includes neutropenia

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:

  1.  To determine the maximum tolerated dose of temozolomide when administered with O6-benzylguanine with and without G-CSF support to pediatric patients with refractory brain tumors stratified by previous radiotherapy.

Secondary:

  1. To characterize the pharmacokinetics of temozolomide and O6-BG when used in combination. 

  2. To characterize toxicities associated with the combination of O6-BG and temozolomide with and without G-CSF support.

  3. To document antitumor response in patients when treated with O6-BG and temozolomide.

  4. 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
Department of Hematology/Oncology
St Jude Children's Research Hospital
332 North Lauderdale Street
Memphis, TN 38105

Friedman, Henry, MD
Duke University Medical Center
Dept. of Pediatrics, Medicine & Surgery
Trent Drive
Durham, NC 27710


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