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

Phase 2TerminatedNCT00436436

National Cancer Institute (NCI)12 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Brain and Central Nervous System Tumors

Eligibility

Sex: ALLMin age: 18 YearsMax age: 120 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Confirmed Best Objective Tumor Response Rate (Complete or Partial Response) in Patients With Methylguanine Methyltransferase (MGMT)-Positive Tumors as Assessed by Immunohistochemistry (IHC)

Time frame: 2-4 weeks

Secondary Outcomes

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).

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: up to 2 years

Overall Survival

Defined as the interval between the day of first administration of treatment and the date of death.

Time frame: up to 2 years

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

Overview

Conditions

Interventions

Eligibility

Locations (2)

Outcomes

Primary Outcomes

Secondary Outcomes