Clinical Trial Finder

DISEASE CHARACTERISTICS:

Inclusion criteria:

• - Histologically proven malignant glioma including any of the following: - Glioblastoma multiforme.

• - Gliosarcoma.

• - Anaplastic astrocytoma.

• - Anaplastic oligodendroglioma.

• - Anaplastic mixed oligoastrocytoma.

• - Malignant astrocytoma not otherwise specified.

• - Unequivocal evidence of tumor recurrence or progression by MRI or CT scan with contrast.

• - No more than one relapse.

• - Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply: - More than 2 weeks from surgery and have recovered from the effects of surgery.

• - Evaluable or measurable disease following resection of recurrent tumor is not mandated for eligibility into the study if a treatment failure can be evaluated.

• - Enhanced CT scan/ MRI should be done no later than 96 hours in the immediate post-operative period or 4-6 weeks post-operatively.

• - If the 96-hour scan is more than 2 weeks from registration, the scan needs to be repeated.

• - A baseline scan should be performed within 14 days prior to registration and on a steroid dosage that has been stable for 5 or more days otherwise a new baseline MRI/CT is required.

• - The same type of scan (i.e., MRI or CT scan) must be used throughout the period of protocol treatment for tumor measurement.

• - Must have failed prior external-beam radiotherapy.

• - Must have failed one prior systemic treatment with chemotherapy or biologic agents.

PATIENT CHARACTERISTICS:

Inclusion criteria:

• - Karnofsky performance status 60-100% - Life expectancy > 12 weeks.

• - WBC > 3,000/mm³ - ANC > 1,500/mm³ - Platelet count > 100,000/mm³ - Hemoglobin > 10 mg/dL.

• - AST and ALT < 4 times upper limit of normal (ULN) - Bilirubin < 2 times ULN.

• - Creatinine < 1.5 times ULN.

• - Fertile patients must use acceptable contraceptive methods (abstinence, intrauterine device [IUD], oral contraceptive or double barrier device) - Negative pregnancy test.

• - Not pregnant or nursing.

Exclusion criteria:

• - Active uncontrolled bleeding.

• - Active infection of any kind.

• - Unwilling or unable to follow protocol requirements or to give informed consent.

• - Active heart disease including any of the following: - Myocardial infarction within the past 3 months.

• - Uncontrolled arrhythmias.

• - Uncontrolled coronary artery disease.

• - Uncontrolled congestive heart failure.

• - Known HIV-positive patients (HIV testing is not required) - History of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix) unless in complete remission and off all therapy for that disease for a minimum of 3 years.

PRIOR CONCURRENT THERAPY:

Inclusion criteria:

• - See Disease Characteristics.

• - Recovered from prior therapy.

• - At least 2 weeks since prior vincristine.

• - More than 4 weeks since prior cytotoxic therapy (6 weeks for nitrosoureas) - More than 4 weeks since prior radiotherapy.

• - More than 4 weeks since prior experimental biologic agents (e.g., EGFR inhibitors, etc) - More than 3 weeks since prior procarbazine administration.

• - More than 2 weeks since prior non-cytotoxic agents (e.g., interferon, tamoxifen, thalidomide, or isotretinoin) - Radiosensitizer does not count.

• - At least 2 weeks since prior and no concurrent enzyme inducing anticonvulsants.

• - If patient is on an enzyme inducing anticonvulsant, they may be converted to a non-enzyme inducing anticonvulsant.

Exclusion criteria:

• - Any other concurrent standard or investigational treatment for cancer, or any other investigational agent for any indication.

- Concurrent disulfiram

OBJECTIVES:

• - To determine the maximum tolerated dose (MTD) of VNP40101M when administered with temozolomide in patients with progressive or relapsed (first relapse) malignant glioma.

(Phase I)

• - To record the toxicities of VNP40101M when administered with temozolomide.

(Phase I and II)

• - To measure the level of AGT expression in peripheral blood monocytes before treatment with temozolomide and just prior to the administration of VNP40101M.

(Phase I and II)

• - To determine MGMT methylation status as well as other methylation patterns in blood and tissue from patients treated with this regimen and correlate with outcome.

(Phase I and II)

• - To determine the 6- and 12-month progression-free survival rates of patients treated with this regimen.

(Phase II)

• - To determine overall survival of patients treated with this regimen.

(Phase II)

• - To determine the complete and partial response rates in patients treated with this regimen.

(Phase II)

• - To determine CSF penetration of VNP40101M once the MTD is reached from phase I and correlate with serum/plasma pharmacokinetics.

(Phase II) OUTLINE:

• - Phase I: Patients receive oral temozolomide on days 1-7 and VNP40101M IV over 15-30 minutes 2 hours after the last dose of temozolomide on day 7.

Treatment repeats every 7 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of VNP40101M until the maximum tolerated dose (MTD) is determined The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose limiting toxicity.

• - Phase II: Patients receive oral temozolomide and VNP40101M as in phase I.

VNP40101M is given at the MTD determined in phase

• I. In both phases, patients complete the Functional Assessment of Cancer Therapy-Brain (FACT-BR) questionnaire on day 1 of each course.

Blood is collected for in vitro isolation of mononuclear cells for analysis of O^6 alkylguanine DNA alkyltransferase on days 1 and 7 of course 1. Blood, plasma, CSF, and formalin-fixed paraffin-embedded tissue blocks are collected for gene methylation studies, including MGMT, at baseline and on day 1 of each course.