O(6)-Benzylguanine and Temozolomide in Treating Patients With Glioblastoma Multiforme That Did Not Respond to Previous Temozolomide and Radiation Therapy

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as O(6)-benzylguanine and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. PURPOSE: This phase II trial is studying the side effects and how well giving O(6)-benzylguanine together with temozolomide works in treating patients with glioblastoma multiforme that did not respond to previous temozolomide and radiation therapy.

Detailed Description
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OBJECTIVES: Determine the antitumor activity of O6-benzylguanine and temozolomide in patients with temozolomide-resistant methylguanine methyltransferase-positive or -negative glioblastoma multiforme previously treated with radiotherapy. Determine, preliminarily, the toxicity of this regimen in these patients. OUTLINE: Patients receive O6-benzylguanine intravenous (IV) over 1 hour and oral temozolomide once daily on days 1-5. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for at least 6 months. PROJECTED ACCRUAL: A total of 100 patients will be accrued for this study.

Official Title
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A Phase 2 Study of O-Benzylguanine (O-BG) and Temozolomide in Patients With Glioblastoma Progressing at Least 3 Months After Completion of Primary Treatment With Radiation Therapy and Temozolomide

Conditions
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Brain and Central Nervous System Tumors

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


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed glioblastoma multiforme (GBM), including the following: Small or large cell GBM Gliosarcoma Temozolomide-resistant disease, as defined by the following: Unequivocal evidence of tumor progression after receiving adjuvant temozolomide therapy for 5 consecutive days every 28 days for ≥ 2 courses Must have failed prior radiotherapy Progression must be documented by MRI (while on a stable steroid dose for ≥ 5 days) ≥ 12 weeks after completion of radiotherapy Must have paraffin-embedded tissue blocks or ≥ 4 unstained paraffin-embedded microscope slides available from diagnosis PATIENT CHARACTERISTICS: Karnofsky performance status 60-100% Life expectancy > 8 weeks White blood cell (WBC) ≥ 3,000/mm(³) Absolute neutrophil count ≥ 1,500/mm(³) Platelet count ≥ 100,000/mm(³) Hemoglobin ≥ 10 g/dL (transfusion allowed) Aspartate aminotransaminase (AST) < 2 times upper limit of normal (ULN) Bilirubin < 2 times ULN Creatinine < 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min No significant medical illness that, in the opinion of the investigator, would preclude study compliance Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No significant active cardiac, hepatic, renal, or psychiatric disease No other known active malignancy except for nonmelanoma skin cancer or carcinoma in situ of the cervix No active infection requiring intravenous (IV) antibiotics No disease that would obscure toxicity or alter drug metabolism PRIOR CONCURRENT THERAPY: See Disease Characteristics Recovered from prior temozolomide Prior resection of recurrent or progressive tumor allowed if all the following criteria are met: Recovered from prior surgery Residual disease after resection of recurrent tumor by computed tomography (CT) scan or magnetic resonance imaging (MRI) (while on a stable steroid dose for ≥ 5 days) ≤ 96 hours OR ≥ 4 weeks after surgery At least 12 weeks since prior radiotherapy No other prior therapy (i.e., polifeprosan 20 with carmustine implant [Gliadel wafers] or nitrosoureas) No other concurrent chemotherapy, radiotherapy, immunotherapy, or investigational agents

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: O6-benzylguanine & Temozolomide in Glioblastoma<br>Patients receive O6-benzylguanine intravenous over 1 hour and oral temozolomide once daily on days 1-5. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: O6-benzylguanine<br> <br> * Other names: 06-BG;Drug: temozolomide<br> <br> * Other names: Temodar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Best Objective Tumor Response Rate (Complete or Partial Response) in Patients With Methylguanine Methyltransferase (MGMT)-Positive Tumors as Assessed by Immunohistochemistry (IHC) | The date of response will be the date the response is first radiographically documented following initiation of therapy (typically, the date of the actual imaging modality). Complete response is complete disappearance of all measurable and evaluable disease. No new lesions. No evidence of non-evaluable disease. Partial response is greater than or equal to a 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable lesions. | 2-4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Tumor Response Rate in Patients With Methylguanine Methyltransferase (MGMT)-Negative Tumors as Assessed by Immunohistochemistry (IHC) | The date of response will be the date the response is first radiographically documented following initiation of therapy (typically, the date of the actual imaging modality). Complete response is complete disappearance of all measurable and evaluable disease. No new lesions. No evidence of non-evaluable disease. Partial response is greater than or equal to a 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable lesions. Stable/No disease does not qualify for CR, PR, or progression. Progression is a 25% increase in the sum of products of all measurable lesions (or two largest lesions if too numerous) over the smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). | 2-4 weeks | 
| Toxicity as Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v 3) | Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module. Adverse events were assessed by the Common Terminology Criteria in Adverse Events (CTCAE)v3. | 18 months and 4 days | 
| Best Overall Response | Defined as the best tumor response recorded from the start of treatment until disease progression or withdrawal from the study. Complete response is complete disappearance of all measurable and evaluable disease. No new lesions. No evidence of non-evaluable disease. Partial response is greater than or equal to a 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable lesions. Stable/No disease does not qualify for CR, PR, or progression. Progression is a 25% increase in the sum of products of all measurable lesions (or two largest lesions if too numerous) over the smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer | up to 2 years | 
| Progression-free Survival | Defined as the interval between the day of first administration of treatment and the first documentation of progressive disease or date of death. Progression is a 25% increase in the sum of products of all measurable lesions (or two largest lesions if too numerous) over the smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer | up to 2 years | 
| Overall Survival | Defined as the interval between the day of first administration of treatment and the date of death. | up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult giant cell glioblastoma, adult gliosarcoma, recurrent adult brain tumor, adult glioblastoma