PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose of O6-benzylguanine when administered with standard high-dose ifosfamide in patients with unresectable, metastatic solid tumors. II. Determine whether O6-benzylguanine enhances ifosfamide-mediated myelosuppression in patients treated with this regimen. III. Determine the relationship between O6-benzylguanine dose and intra-individual variability in the degree of myelosuppression in patients treated with this regimen. IV. Determine the safety and toxicity of this regimen in these patients. SECONDARY OBJECTIVES: I. Determine the effect of O6-benzylguanine on pharmacodynamic endpoints, including apoptosis and DNA damage, in patients treated with this regimen. II. Determine the pharmacokinetics of O6-benzylguanine and its major metabolite, 8-oxoBG, in patients treated with this regimen. OUTLINE: This is a randomized, open-label, multicenter, dose-escalation study of O6-benzylguanine. Course 1: All patients receive high-dose ifosfamide IV continuously over 72 hours on days 1-3. Course 2: Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive high-dose ifosfamide as in course 1. Arm II: Patients receive a bolus dose of O6-benzylguanine (BG) IV over 1 hour on day 1 followed by BG IV continuously and high-dose ifosfamide IV continuously over 72 hours on days 1-3. Cohorts of 6-12 patients receive escalating doses of BG (administered as a bolus and as a continuous infusion during course 2) until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 3 of 6 or 4 of 12 patients experience dose-limiting toxicity. Course 3 and all subsequent courses: All patients receive BG (at the MTD determined in course 2, arm II) and high-dose ifosfamide as in course 2, arm II. In all courses, all patients also receive filgrastim (G-CSF) beginning on day 5 and continuing until blood counts recover. In all courses and in both arms, treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
Inclusion Criteria: * Histologically confirmed solid tumor * Unresectable, metastatic disease * No primary tumors * Eligible for high-dose ifosfamide-based therapy * No known brain metastases * Performance status - ECOG 0-1 * Performance status - Karnofsky 70-100% * More than 12 weeks * Absolute neutrophil count ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * AST and ALT ≤ 2.5 times upper limit of normal * Bilirubin normal * Creatinine normal * Creatinine clearance ≥ 60 mL/min * No symptomatic congestive heart failure * No unstable angina pectoris * No cardiac arrhythmia * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for 4 weeks after study participation * No history of allergic reaction attributed to compounds of similar chemical or biological composition to O6-benzylguanine or other study agents * No concurrent uncontrolled illness * No active or ongoing infection * No psychiatric illness or social situation that would preclude study compliance * More than 24 hours since prior colony-stimulating factors (filgrastim \[G-CSF\] or sargramostim \[GM-CSF\]) * No prior hematopoietic stem cell transplantation * No concurrent pegfilgrastim * No concurrent immunotherapy * More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered * No other concurrent chemotherapy * No concurrent hormonal therapy * More than 4 weeks since prior radiotherapy and recovered * No concurrent therapeutic radiotherapy * More than 4 weeks since prior anticancer therapy * No more than 2 prior cytotoxic regimens * No concurrent combination antiretroviral therapy for HIV-positive patients * No other concurrent anticancer agents or therapies * No other concurrent investigational agents
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