Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00052780
First received: January 24, 2003
Last updated: September 27, 2013
Last verified: September 2013
  Purpose

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


Condition Intervention Phase
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
Drug: O6-benzylguanine
Drug: temozolomide
Biological: filgrastim
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Trial of Temozolomide and O6-Benzylguanine in Pediatric Patients With Recurrent Brain Tumors

Resource links provided by NLM:


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

Primary Outcome Measures:
  • MTD of temozolomide [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Pharmacokinetic parameters [ Time Frame: Baseline and courses 1 and 3 ] [ Designated as safety issue: No ]
    Summarized using descriptive statistics (mean, standard deviation) if normally distributed. For log-normally distributed data, the geometric mean will be used. If the data are not normally distributed, nonparametric statistics (median, minimum, maximum, interquartile ranges) will be used. Logistic regression models will be used to explore possible relationships between the systemic exposure to temozolomide, O6-benzylguanine, and their respective metabolites and toxicities and antitumor activity.

  • Acute toxicities [ Time Frame: 4 weeks (course 1) ] [ Designated as safety issue: Yes ]
    These toxicities will be tabulated according to dose level.

  • Chronic toxicities [ Time Frame: Up to 30 days post-treatment ] [ Designated as safety issue: Yes ]
    Tabulated according to dose level and course of therapy.

  • Histological response [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Exact confidence interval estimates of traditional response by histologic tumor type will be developed.

  • Duration of disease control [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Kaplan-Meier estimates will also be provided.

  • Survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Kaplan-Meier estimates will also be provided.


Enrollment: 72
Study Start Date: October 2002
Primary Completion Date: November 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (temozolomide, O6-benzylguanine)
See Detailed Description
Drug: O6-benzylguanine
Given IV
Other Name: BG
Drug: temozolomide
Given PO
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • TMZ
Biological: filgrastim
Given SC or IV
Other Names:
  • G-CSF
  • Neupogen
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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.

  Eligibility

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

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 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
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

Locations
United States, Tennessee
Pediatric Brain Tumor Consortium
Memphis, Tennessee, United States, 38105
Sponsors and Collaborators
Investigators
Principal Investigator: Amar Gajjar Pediatric Brain Tumor Consortium
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00052780     History of Changes
Other Study ID Numbers: NCI-2012-03174, NCI-2012-03174, CDR653709, PBTC-005, PBTC-005, U01CA081457
Study First Received: January 24, 2003
Last Updated: September 27, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Adamantinoma
Astrocytoma
Brain Neoplasms
Choroid Plexus Neoplasms
Craniopharyngioma
Ependymoma
Glioma
Medulloblastoma
Meningioma
Neoplasms
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Oligodendroglioma
Optic Nerve Glioma
Bone Diseases
Bone Neoplasms
Brain Diseases
Central Nervous System Diseases
Central Nervous System Neoplasms
Cerebral Ventricle Neoplasms
Cranial Nerve Diseases
Cranial Nerve Neoplasms
Eye Diseases
Meningeal Neoplasms
Musculoskeletal Diseases
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue

ClinicalTrials.gov processed this record on November 24, 2014