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

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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

Brief Summary: 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.

Detailed Summary:

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
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome: MTD of temozolomide [ Time Frame: 28 days ]

Original Primary Outcome:

Current Secondary Outcome:

  • Pharmacokinetic parameters [ Time Frame: Baseline and courses 1 and 3 ]
    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) ]
    These toxicities will be tabulated according to dose level.
  • Chronic toxicities [ Time Frame: Up to 30 days post-treatment ]
    Tabulated according to dose level and course of therapy.
  • Histological response [ Time Frame: Up to 5 years ]
    Exact confidence interval estimates of traditional response by histologic tumor type will be developed.
  • Duration of disease control [ Time Frame: Up to 5 years ]
    Kaplan-Meier estimates will also be provided.
  • Survival [ Time Frame: Up to 5 years ]
    Kaplan-Meier estimates will also be provided.


Original Secondary Outcome:

Information By: National Cancer Institute (NCI)

Dates:
Date Received: January 24, 2003
Date Started: October 2002
Date Completion:
Last Updated: September 27, 2013
Last Verified: September 2013