Protocol Number: 07-C-0052

Title:

A Phase 2 Study of O6-Benzylguanine (O(6)-BG) and Temozolomide in Patients with Glioblastoma Progressing at Least 3 Months After Completion of Primary Treatment with Radiation Therapy and Temozolomide

Number:

07-C-0052

Summary:

Background:

High grade gliomas represent an important cause of cancer morbidity and mortality in this country. Despite progress in neurosurgical and radiotherapeutic techniques, there has been little improvement in the overall prognosis of patients with high grade gliomas in the last 20 years. Standard chemotherapy is of limited benefit in this disease and thus new targets and agents with novel mechanisms of action are needed.

Temozolomide has become a standard treatment for patients with gliomas including glioblastoma. It is approved for first line treatment of glioblastoma in combination with radiation therapy and as second line treatment for patients with anaplastic astrocytoma. A primary mechanism of resistance to temozolomide is the repair of DNA damaging lesions by the protein Methylguanine Methyl Transferase (MGMT). O6-Benzylguanine (O6-BG) provides a competitive substrate for MGMT. Once an MGMT molecule is bound to O6-BG it becomes permanently unable to repair lesions caused by temozolomide. Thus, O6-BG may be able to reverse MGMT-mediated temozolomide resistance.

Objectives:

This study is designed to evaluate the response rate to 5 days of temozolomide combined with O6-BG in patients with glioblastomas who have progressed at least 12 weeks after completion of radiotherapy with temozolomide and are currently receiving standard post-radiotherapy temozolomide. The primary endpoint will be to evaluate the combination in patients who have been demonstrated to have MGMT positive tumors by immunohistochemistry. As a secondary endpoint, the response rate will also be determined in those patients who have MGMT negative tumors by immunohistochemistry.

Eligibility:

Patients with glioblastoma whose disease has progressed while receiving adjuvant temozolomide and at least 3 months after completing radiation therapy will be entered into a phase 2 study of temozolomide and O6-BG.

Design:

O6-BG 120 mg/m(2) will be administered intravenously over 1 hour for five consecutive days. For the first two cycles of therapy, temozolomide at a dose of 50 mg/m(2) will be administered orally, in a fasting state (minimum of 2 hours from last meal) within 60 minutes of the end of each infusion of O6-BG. In the absence of grade 3 or 4 hematologic toxicities, the dose will be escalated to 75 mg/m(2) for subsequent cycles. Temozolomide and O6-BG will be administered on days 1 to 5 of the treatment cycle with treatment cycles repeated every 28 days.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

Patients with histologically proven glioblastoma multiforme (GBM) and its variants including small and large cell GBM and gliosarcoma.

Patients must have unequivocal evidence for tumor progression while receiving adjuvant temozolomide therapy given as a dose of 150-200 mg/m(2) for 5 consecutive days every 28 days for at least the last two cycles prior to tumor progression. Progression will be documented by MRI scan. Progression should be documented at least 12 weeks after completion of radiotherapy. An MRI scan will be performed within 14 days prior to registration and on a steroid dosage that has been stable for at least 5 days. If the steroid dose is increased between the date of imaging and registration a new baseline MRI scan is required.

Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply:

They have recovered from the effects of surgery.

Residual disease following resection of recurrent tumor is mandated for eligibility into the study. To best assess the extent of residual disease post-operatively, a CT/MRI should be done:

no later than 96 hours in the immediate post-operative period or

at least 4 weeks post-operatively, and

within 14 days of registration, and

on a steroid dosage that has been stable for at least 5 days.

If the steroid dose is increased between the date of imaging and registration, a new baseline MRI/CT is required on a stable steroid dosage for at least 5 days.

Patients must have failed prior radiation therapy and must have an interval of greater than or equal to 12 weeks from the completion of radiation therapy to study entry.

Patients may not have had any other therapy for their glioma other than surgery, radiation therapy and temozolomide (i.e. no Gliadel wafers or nitrosoureas)

All patients or their previously designated DPA (if the patient is deemed by the treating physician to be cognitively impaired or questionably impaired in such a way that the ability of the patient to give informed consent is questionable) must sign an informed consent indicating they are aware of the investigational nature of this study.

Patients must be greater than or equal to 18 years old, and with a life expectancy greater than 8 weeks.

KPS of greater than or equal to 60 is mandatory.

Patients must have recovered from the toxic effects of prior temozolomide therapy.

Patients must have adequate bone marrow function (WBC greater than or equal to 3,000/microliter, ANC greater than or equal to 1,500/microliter, platelet count of greater than or equal to 100,000/microliter and hemoglobin greater than or equal to 10 gm/dl), adequate liver function (AST and bilirubin less than 2 times ULN), and adequate renal function (creatinine less than 1.5 mg/dL and/or creatinine clearance greater than or equal to 60 cc/min) before starting therapy. These tests must be performed within 14 days prior to registration. Eligibility level for hemoglobin may be reached by transfusion.

Patients must not have any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patients' ability to tolerate this therapy.

This study was designed to include women and minorities, but was not designed to measure differences of intervention effects. Males and females will be recruited with no preference to gender. No exclusion to this study will be based on race.

Patients must have available from diagnosis paraffin-embedded tissue blocks or at least 4 unstained paraffin-embedded microscope slides that can be sent to the Neuro-Oncology Branch who will then catalog the slides and forward them to the Department of Pathology at Duke Medical Center for determination of their tumors MGMT status. The results of the MGMT immunohistochemistry testing is not required prior to being registered for the study or starting therapy. If the patient has had more than one surgery for their GBM, the MGMT status will be based on the most recent tumor specimen that is available for MGMT assessment (i.e. if the patient has had two surgeries, the MGMT status will be assessed and used from the second surgery if that tissue block is available. If that tissue block is not available, then tumor tissue from the first surgery may be utilized).

Patients must practice adequate contraception.

EXCLUSION CRITERIA:

Patients who, in the view of the treating physician, have significant active cardiac, hepatic, renal, or psychiatric diseases are ineligible.

No concurrent use of other standard chemotherapeutics or investigative agents.

Patients known to have an active malignancy (except non-melanoma skin cancer or carcinoma in-situ of the cervix).

Patients who have an active infection requiring IV antibiotics.

Patients who are pregnant or breast feeding.

Patients who have any disease that will obscure toxicity or dangerously alter drug metabolism.

Special Instructions:

Currently Not Provided

Keywords:

Brain

Tumor

Cytotoxic

Intravenous

Chemotherapy

Recruitment Keyword(s):

Brain Tumor

Glioblastoma

Condition(s):

Glioblastoma Multiforme

Large Cell Glioblastoma

Glosarcoma

Investigational Drug(s):

O(6) Benzylguanine (06BG)

Investigational Device(s):

None

Intervention(s):

Drug: O(6) Benzylguanine (06BG)

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Soffietti R, Nobile M, Ruda R, Borgognone M, Costanza A, Laguzzi E, Mutani R. Second-line treatment with carboplatin for recurrent or progressive oligodendroglial tumors after PCV (procarbazine, lomustine, and vincristine) chemotherapy: a phase II study. Cancer. 2004 Feb 15;100(4):807-13

Prados MD, Warnick RE, Mack EE, Chandler KL, Rabbitt J, Page M, Malec M. Intravenous carboplatin for recurrent gliomas. A dose-escalating phase II trial. Am J Clin Oncol. 1996 Dec;19(6):609-12

Hochberg FH, Pruitt A. Assumptions in the radiotherapy of glioblastoma. Neurology. 1980 Sep;30(9):907-11

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