Bortezomib in Treating Patients With Recurrent Glioma

Study Overview
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Brief Summary
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Phase I trial to study the effectiveness of bortezomib in treating patients who have recurrent glioma. Bortezomib may stop the growth of tumor cells by blocking the enzymes necessary for tumor cell growth

Detailed Description
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OBJECTIVES: I. Determine the maximum tolerated dose of bortezomib with or without anticonvulsant drugs known to be metabolized by the P450 hepatic enzyme complex in patients with recurrent glioma. II. Determine the biologic activity of this drug by measuring proteasome 20S activity in these patients. III. Determine the effects of hepatic enzyme-inducing drugs, such as anticonvulsants, on biologic activity of this drug in these patients. OUTLINE: This is a dose-escalation, multicenter study. Patients are stratified according to concurrent anticonvulsant drug use (phenytoin, carbamazepine, phenobarbital, primidone, or felbamate vs gabapentin, lamotrigine, valproic acid, or no anticonvulsant drugs). Patients receive bortezomib IV over 3-5 seconds twice weekly for 2 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of bortezomib 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. Once the MTD is determined, 10 additional patients are treated with bortezomib at the MTD. Patients are followed every 2 months.

Official Title
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Phase I Evaluation of the Safety of PS 341 in the Treatment of Recurrent Gliomas

Conditions
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Adult Anaplastic Astrocytoma, Adult Anaplastic Oligodendroglioma, Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor

Intervention / Treatment
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* Drug: bortezomib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed progressive or recurrent malignant glioma Anaplastic astrocytoma Anaplastic oligodendroglioma Glioblastoma multiforme Prior low-grade gliomas that have progressed to high-grade after therapy allowed Measurable disease by MRI or CT scan Performance status - Karnofsky 60-100% Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Bilirubin no greater than 1.5 mg/dL Transaminases no greater than 4 times upper limit of normal Creatinine no greater than 1.7 mg/dL Mini mental score at least 15 No concurrent serious infection or other medical illness that would preclude study participation No other malignancy within the past 5 years except curatively treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after study participation At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas) and recovered No more than 1 prior chemotherapy regimen At least 3 months since prior radiotherapy and recovered 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (bortezomib)<br>Patients receive bortezomib IV over 3-5 seconds twice weekly for 2 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. | Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of bortezomib defined as the dose level below that at which > 1 of 3-6 patients experience DLT | Graded using the CTC version 2.0. | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biological effectiveness estimated using 20S proteosome activity | Simple descriptive measures will be used to examine the association between biological effect and the probability of toxicity and response. | Up to 6 years | 
| Frequency of toxicity, graded using the CTC version 2.0 | The proportion of patients with serious or life threatening toxicities will be estimated along with 95% confidence intervals. | Up to 6 years |