O(6)-Benzylguanine and Carmustine in Treating Patients With Solid Tumors

Overview

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. PURPOSE: Phase I trial to study the effectiveness of O(6)-benzylguanine and carmustine in treating patients who have solid tumors.

OBJECTIVES: I. Determine the biochemical modulation dose l of O6-benzylguanine (BG), defined as the dose at which baseline O6-alkylguanine DNA alkyltransferase (AGT) activity in circulating peripheral blood mononuclear cells (PBMC) decreases by greater than 90% in patients with advanced solid tumors at 2 hours after BG infusion. II. Determine the biochemical modulation dose t/18 (BMDt/18) of BG, defined as the dose at which AGT activity in human metastatic tumor tissue decreases to undetectable levels at 18 hours after BG infusion. III. Determine the maximum tolerated dose of carmustine (BCNU) when administered with BG at the BMDt/18 in these patients. IV. Determine the toxicities of BG and BCNU in these patients. V. Determine the pharmacokinetic parameters of BG administered at the BMDt/18, and determine any effects of BCNU on BG pharmacokinetics. VI. Assess any antitumor response in patients with metastatic solid tumors treated with this regimen. VII. Determine the effect of lower, more frequent bolus doses or a continuous infusion of BG on the depletion of AGT activity in PBMC and tumor tissue in these patients. VIII. Determine the pharmacokinetics of BG in lower, more frequent bolus doses or continuous infusion. OUTLINE: This is a dose escalation study of 06-benzylguanine (BG) and carmustine (BCNU). Patients receive BG IV over 1 hour during week 1, and then BG IV over 1 hour followed 1 hour later by BCNU IV over 1 hour during week 3. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 1-3 patients receive escalating doses of BG until the biochemical modulation dose l (BMDl) is determined. The BMDl is defined as the dose at which baseline O6-alkylguanine DNA alkyltransferase (AGT) activity in circulating peripheral blood mononuclear cells decreases by greater than 90% at 2 hours after BG infusion. Cohorts of 3 patients receive escalating doses of BG beginning at the BMDl until the biochemical modulation dose t/2 (BMDt/2) is determined. The BMDt/2 is defined as the dose at which AGT activity in human metastatic tumor tissue decreases by greater than 90% at 2 hours after BG infusion. Cohorts of 3 patients receive escalating doses of BG beginning at the BMDt/2 until the biochemical modulation dose t/18 (BMDt/18) is determined. The BMDt/18 is defined as the dose at which AGT activity in human metastatic tumor tissue decreases to undetectable levels at 18 hours after BG infusion. Patients then receive BG IV over 1 hour followed 1 hour later by BCNU IV over 1 hour during week 1. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of BCNU combined with BG at the BMDt/18 until the maximum tolerated dose (MTD) of BCNU is determined. The MTD of BCNU is defined as the dose preceding that at which 2 or more of 6 patients experience dose limiting toxicity. A cohort of 3 patients receives BG IV over 2 minutes and another cohort of 3 patients receives BG IV over 24 hours. An additional cohort of 6 patients receives BG IV over 24 hours and BCNU IV over 1 hour beginning 2 hours into BG infusion during week 3. PROJECTED ACCRUAL: A total of 51 patients will be accrued for this study over 36 months.

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Outcomes