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

2014-07-24 14:33:15 | BioPortfolio

Summary

RATIONALE: 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.

PURPOSE: 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.

Description

OBJECTIVES:

Primary

- Determine the maximum tolerated dose of O6-benzylguanine when administered with standard high-dose ifosfamide in patients with unresectable, metastatic solid tumors.

- Determine whether O6-benzylguanine enhances ifosfamide-mediated myelosuppression in patients treated with this regimen.

- Determine the relationship between O6-benzylguanine dose and intra-individual variability in the degree of myelosuppression in patients treated with this regimen.

- Determine the safety and toxicity of this regimen in these patients.

Secondary

- Determine the effect of O6-benzylguanine on pharmacodynamic endpoints, including apoptosis and DNA damage, in patients treated with this regimen.

- 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.

PROJECTED ACCRUAL: A minimum of 32 patients (at least 2 in arm I and at least 24 in arm II) will be accrued for this study within 12-15 months.

Study Design

Allocation: Randomized, Control: Active Control, Masking: Open Label, Primary Purpose: Treatment

Conditions

Unspecified Adult Solid Tumor, Protocol Specific

Intervention

filgrastim, O6-benzylguanine, ifosfamide

Location

University of Chicago Cancer Research Center
Chicago
Illinois
United States
60637-1470

Status

Completed

Source

National Cancer Institute (NCI)

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-07-24T14:33:15-0400

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Medical and Biotech [MESH] Definitions

A solid, unencapsulated tumor of the KIDNEY composed of spindle mesenchymal cells that resemble FIBROBLASTS or muscle cells. The homogeneous mass typically extends into the renal parenchyma and replaces most of the kidney. In most cases, mesoblastic nephroma is benign and occurs in the fetus or newborn, and rarely in the older child or the adult.

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A malignant cystic or semisolid tumor most often occurring in the ovary. Rarely, one is solid. This tumor may develop from a mucinous cystadenoma, or it may be malignant at the onset. The cysts are lined with tall columnar epithelial cells; in others, the epithelium consists of many layers of cells that have lost normal structure entirely. In the more undifferentiated tumors, one may see sheets and nests of tumor cells that have very little resemblance to the parent structure. (Hughes, Obstetric-Gynecologic Terminology, 1972, p184)

A solid tumor consisting of a dense infiltration of MAST CELLS. It is generally benign.

An adenocarcinoma in which the tumor elements are arranged as finger-like processes or as a solid spherical nodule projecting from an epithelial surface.

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