Ifosfamide With or Without O(6)-Benzylguanine in Treating Patients With Unresectable, Metastatic Solid Tumors

Study Overview
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Brief Summary
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This randomized phase I trial is studying the side effects and best dose of O(6)-benzylguanine when given together with ifosfamide and to see how well it works compared to ifosfamide alone in treating patients with unresectable metastatic solid tumors. Drugs used in chemotherapy, such as ifosfamide and O(6)-benzylguanine, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining ifosfamide with O(6)-benzylguanine may kill more tumor cells

Detailed Description
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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.

Official Title
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A Phase I Study Of BG In Combination With Ifosfamide For Advanced Solid Tumors

Conditions
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Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: ifosfamide
* Drug: O6-benzylguanine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (ifosfamide)<br>Patients receive high-dose ifosfamide IV continuously over 72 hours on days 1-3. | Drug: ifosfamide<br>* Given IV<br>* Other names: IPP;|
| Experimental: Arm II (O6-benzylguanine, ifosfamide)<br>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. | Drug: ifosfamide<br>* Given IV<br>* Other names: IPP;Drug: O6-benzylguanine<br>* Given IV<br>* Other names: BG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in degree of myelosuppression (thrombocytopenia and neutropenia) quantified by both duration of neutropenia and severity of neutropenia |  | Baseline up to 1 year | 
| Maximum tolerated dose (MTD) of O6-benzylguanine defined as the dose preceding that at which 3 of 6 or 4 of 12 patients experience dose-limiting toxicity | DLT is defined as any >= grade 3 non-hematologic toxicity, grade 4 thrombocytopenia, or prolonged neutropenia. | 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamics including apoptosis and DNA damage |  | Up to 1 year | 
| Pharmacokinetics of O6-benzylguanine | Summarized using descriptive statistics (mean, median, standard deviation, and interquartile range). Estimated via nonlinear regression. | Up to day 3 of course 2 |