Temozolomide and O6-Benzylguanine in Treating Children With Recurrent Brain Tumors - Full Text View

Sponsors and Collaborators:	Pediatric Brain Tumor Consortium National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00052780

Purpose

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. O6-benzylguanine may increase the effectiveness of temozolomide by making tumor cells more sensitive to the drug.

PURPOSE: Phase I trial to study the effectiveness of combining O6-benzylguanine with temozolomide in treating children who have recurrent or refractory brain tumors.

Condition	Intervention	Phase
Brain and Central Nervous System Tumors	Biological: filgrastim Drug: O6-benzylguanine Drug: temozolomide	Phase I

Study Type:	Interventional
Study Design:	Treatment
Official Title:	Phase I Trial of Temozolomide and O6-Benzylguanine in Pediatric Patients With Recurrent Brain Tumors

Resource links provided by NLM:

MedlinePlus related topics: Brain Cancer Cancer Childhood Brain Tumors

Drug Information available for: O(6)-Benzylguanine Temozolomide Filgrastim

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Maximum tolerated dose (MTD) after first 4 weeks of treatment [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Best response rate from start of treatment until disease progression/recurrence or three months after completion of study treatment [ Designated as safety issue: No ]

Study Start Date:	December 2002
Primary Completion Date:	November 2007 (Final data collection date for primary outcome measure)

Detailed Description:

OBJECTIVES:

Determine the maximum tolerated dose of temozolomide when administered with O6-benzylguanine (O^6-BG) with and without filgrastim (G-CSF) in pediatric patients with recurrent brain tumors.
Determine the toxic effects of this regimen in these patients.
Determine the pharmacokinetics of temozolomide and O^6-BG in these patients.
Determine the antitumor response of patients treated with temozolomide and O^6-BG.
Correlate MGMT enzyme and mismatch repair protein levels in tumor tissue with outcome in patients treated with this regimen.

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). 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).

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, 12 additional patients are treated at that dose.

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.

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 every 3 months for 1 year and then every 6 months for 4 years.

PROJECTED ACCRUAL: A total of 72 patients (18 per stratum) will be accrued for this study within 3 years.

Eligibility

Ages Eligible for Study:	up to 21 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Histologically confirmed recurrent or refractory brain tumor
- Histological confirmation waived for brain stem gliomas
Bone marrow involvement by disease allowed

PATIENT CHARACTERISTICS:

Age

21 and under

Performance status

Karnofsky 60-100% OR
Lansky 60-100%

Life expectancy

More than 8 weeks

Hematopoietic

Absolute neutrophil count greater than 1,000/mm^3
Platelet count greater than 100,000/mm^3*
Hemoglobin greater than 8 g/dL* NOTE: *Transfusion independent

Hepatic

Bilirubin normal
AST and ALT less than 2.5 times normal
No overt hepatic disease

Renal

Creatinine no greater than 1.5 times normal OR
Glomerular filtration rate greater than 70 mL/min
No overt renal disease

Cardiovascular

No overt cardiovascular disease

Pulmonary

No overt pulmonary disease

Other

Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
Neurological deficits allowed provided they have been stable for at least 1 week prior to study
No uncontrolled infection
No hypersensitivity to dacarbazine, temozolomide, or polyethylene glycol
No grade 3 or 4 nonhematopoietic toxicity with prior temozolomide

PRIOR CONCURRENT THERAPY:

Biologic therapy

Recovered from prior biologic therapy
No more than 2 prior biologic therapy regimens
At least 6 months since prior bone marrow transplantation
At least 3 weeks since prior biologic therapy
More than 2 weeks since prior colony-stimulating factor therapy (e.g., filgrastim [G-CSF], sargramostim [GM-CSF], or epoetin alfa)

Chemotherapy

Recovered from prior chemotherapy
No more than 2 prior chemotherapy regimens
More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas)
More than 3 months since prior temozolomide

Endocrine therapy

Concurrent dexamethasone allowed provided dose has been stable for at least 1 week prior to study

Radiotherapy

At least 3 months since prior craniospinal radiotherapy (at least 18 Gy)
At least 4 weeks since prior local radiotherapy to the primary tumor
At least 2 weeks since prior focal irradiation to symptomatic metastatic sites

Surgery

Not specified

Other

No other concurrent anticancer or experimental drugs
Concurrent anticonvulsants allowed

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00052780

Locations

United States, California
UCSF Comprehensive Cancer Center
San Francisco, California, United States, 94143
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010-2970
United States, Illinois
Children's Memorial Hospital - Chicago
Chicago, Illinois, United States, 60614
United States, Maryland
Warren Grant Magnuson Clinical Center - NCI Clinical Studies Support
Bethesda, Maryland, United States, 20892-1182
United States, Massachusetts
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, North Carolina
Duke Comprehensive Cancer Center
Durham, North Carolina, United States, 27710
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104-4318
Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
United States, Texas
Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital
Houston, Texas, United States, 77030-2399
United States, Washington
Children's Hospital and Regional Medical Center - Seattle
Seattle, Washington, United States, 98105

Sponsors and Collaborators

Pediatric Brain Tumor Consortium

National Cancer Institute (NCI)

Investigators

Study Chair:

Amar Gajjar, MD

St. Jude Children's Research Hospital

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Publications:

Broniscer A, Gururangan S, MacDonald TJ, Goldman S, Packer RJ, Stewart CF, Wallace D, Danks MK, Friedman HS, Poussaint TY, Kun LE, Boyett JM, Gajjar A. Phase I trial of single-dose temozolomide and continuous administration of o6-benzylguanine in children with brain tumors: a pediatric brain tumor consortium report. Clin Cancer Res. 2007 Nov 15;13(22 Pt 1):6712-8.

Study ID Numbers:	CDR0000258738, PBTC-005
Study First Received:	January 24, 2003
Last Updated:	February 6, 2009
ClinicalTrials.gov Identifier:	NCT00052780 History of Changes
Health Authority:	United States: Federal Government

Keywords provided by National Cancer Institute (NCI):

recurrent childhood brain stem glioma
recurrent childhood cerebellar astrocytoma
recurrent childhood cerebral astrocytoma
recurrent childhood ependymoma
recurrent childhood medulloblastoma
recurrent childhood supratentorial primitive neuroectodermal tumor
recurrent childhood visual pathway and hypothalamic glioma

childhood grade I meningioma
childhood grade II meningioma
childhood grade III meningioma
childhood oligodendroglioma
childhood craniopharyngioma
childhood central nervous system germ cell tumor
childhood choroid plexus tumor

Study placed in the following topic categories:

Choroid Plexus Neoplasms
Neuroectodermal Tumors, Primitive
Astrocytoma
Central Nervous System Diseases
Central Nervous System Neoplasms
Brain Diseases
Temozolomide
Recurrence
Ependymoma
Brain Neoplasms
Neuroectodermal Tumors

Brain Stem Glioma, Childhood
Medulloblastoma
Craniopharyngioma
Neuroepithelioma
O(6)-benzylguanine
Oligodendroglioma
Meningioma
Antineoplastic Agents, Alkylating
Glioma
Alkylating Agents
Nervous System Neoplasms

Additional relevant MeSH terms:

Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Nervous System Diseases
Central Nervous System Diseases
Enzyme Inhibitors
Central Nervous System Neoplasms
Brain Diseases
Temozolomide
Pharmacologic Actions

Brain Neoplasms
Neoplasms
Neoplasms by Site
Therapeutic Uses
O(6)-benzylguanine
Antineoplastic Agents, Alkylating
Alkylating Agents
Nervous System Neoplasms

ClinicalTrials.gov processed this record on July 02, 2009