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Phase I Trial of Temozolomide and O6-Benzylguanine in Pediatric Patients With Recurrent Brain Tumors

Phase 1
21 Years
Not Enrolling
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

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Trial Information

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
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.

Inclusion 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

- Karnofsky or Lansky ≥ 60%

- Life expectancy > 8 weeks

- 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

- 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

- ANC > 1,000/μl

- Platelets > 100,000/μl

- Hemoglobin > 8g/dl

- Patients may have bone marrow involvement by disease; platelet and Hgb counts must be
transfusion independent

- Creatinine ≤ 1.5 times institutional normal for age

- Or GFR > 70 ml/min/1.73m^2

- Bilirubin ≤ upper limit of normal for age

- SGPT (ALT) < and SGOT (AST) < 2.5X institutional normal

- No overt renal, hepatic, cardiac or pulmonary disease

- Female patients of childbearing potential must have negative serum or urine pregnancy
test; patient must not be pregnant or breast-feeding; while no known teratogenic
effects are known for O6-BG so far, there is little data to address this
specifically; as such, the prudent approach is to exclude pregnant and breastfeeding
patients until further data is available

- Patients of childbearing or child-fathering potential must be willing to use a
medically acceptable form of birth control, which includes abstinence, while being
treated on this study

- Signed informed consent according to institutional guidelines must be obtained and
patients must begin therapy within seven (7) days of registration

Exclusion Criteria:

- Patients must not be receiving any other anticancer or experimental drug therapy

- Patients with a history of hypersensitivity to dacarbazine, temozolomide or
polyethylene glycol are excluded

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD of temozolomide

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Amar Gajjar

Investigator Role:

Principal Investigator

Investigator Affiliation:

Pediatric Brain Tumor Consortium


United States: Food and Drug Administration

Study ID:




Start Date:

October 2002

Completion Date:

Related Keywords:

  • 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
  • Astrocytoma
  • Brain Neoplasms
  • Craniopharyngioma
  • Adamantinoma
  • Ependymoma
  • Glioma
  • Medulloblastoma
  • Meningioma
  • Oligodendroglioma
  • Choroid Plexus Neoplasms
  • Neoplasms, Germ Cell and Embryonal
  • Pinealoma
  • Neuroectodermal Tumors
  • Neuroectodermal Tumors, Primitive
  • Optic Nerve Glioma



Pediatric Brain Tumor Consortium Memphis, Tennessee  38105