Clinical trial NCT00436436: O(6)-Benzylguanine and Temozolomide in Treating Patients With Glioblastoma Multiforme That Did Not Respond to Previous Temozolomide and Radiation Therapy
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Brain and Central Nervous System Tumors
Keywords: adult giant cell glioblastoma
adult gliosarcoma
recurrent adult brain tumor
adult glioblastoma
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2007-02-19
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Confirmed Best Objective Tumor Response Rate (Complete or Partial Response) in Patients With Methylguanine Methyltransferase (MGMT)-Positive Tumors as Assessed by Immunohistochemistry (IHC)
timeFrame: 2-4 weeks
Secondary outcomes:
measure: Objective Tumor Response Rate in Patients With Methylguanine Methyltransferase (MGMT)-Negative Tumors as Assessed by Immunohistochemistry (IHC)
timeFrame: 2-4 weeks
measure: Toxicity as Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v 3)
timeFrame: 18 months and 4 days
measure: Best Overall Response
timeFrame: up to 2 years
measure: Progression-free Survival
timeFrame: up to 2 years
measure: Overall Survival
timeFrame: up to 2 years
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
state: Maryland
city: Bethesda
country: United States
facility: NCI - Neuro-Oncology Branch
state: Maryland
Study officials:
affiliation: NCI - Neuro-Oncology Branch
name: Howard A Fine, M.D.
role: PRINCIPAL_INVESTIGATOR
References: