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

This study has been terminated.
(Study closed to accrual after the company chose to stop development of the drug.)
Sponsor:
ClinicalTrials.gov Identifier:
NCT00436436
First Posted: February 19, 2007
Last Update Posted: March 28, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Mark Gilbert, M.D., National Institutes of Health Clinical Center (CC)
  Purpose

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.


Condition Intervention Phase
Brain and Central Nervous System Tumors Drug: O6-benzylguanine Drug: temozolomide Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Mark Gilbert, M.D., National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • 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 ]
    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.


Secondary Outcome Measures:
  • Objective Tumor Response Rate in Patients With Methylguanine Methyltransferase (MGMT)-Negative Tumors as Assessed by Immunohistochemistry (IHC) [ Time Frame: 2-4 weeks ]
    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).

  • Toxicity as Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v 3) [ Time Frame: 18 months and 4 days ]
    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.

  • Best Overall Response [ Time Frame: up to 2 years ]
    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

  • Progression-free Survival [ Time Frame: up to 2 years ]
    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

  • Overall Survival [ Time Frame: up to 2 years ]
    Defined as the interval between the day of first administration of treatment and the date of death.


Enrollment: 12
Actual Study Start Date: November 13, 2006
Study Completion Date: April 14, 2010
Primary Completion Date: March 15, 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: O6-benzylguanine & Temozolomide in Glioblastoma
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
Other Name: 06-BG
Drug: temozolomide
Other Name: Temodar

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

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 120 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00436436


Locations
United States, Maryland
Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
Bethesda, Maryland, United States, 20892-1182
NCI - Neuro-Oncology Branch
Bethesda, Maryland, United States, 20892-8200
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Howard A Fine, M.D. NCI - Neuro-Oncology Branch
  More Information

Responsible Party: Mark Gilbert, M.D., Branch Chief, Neuro-Oncology Branch, National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT00436436     History of Changes
Other Study ID Numbers: 070052
NCI-07-C-0052
AOI-NCI-07-C-0052
CDR0000529875 ( Other Identifier: nci )
First Submitted: February 15, 2007
First Posted: February 19, 2007
Results First Submitted: November 25, 2016
Results First Posted: March 28, 2017
Last Update Posted: March 28, 2017
Last Verified: February 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Mark Gilbert, M.D., National Institutes of Health Clinical Center (CC):
adult giant cell glioblastoma
adult gliosarcoma
recurrent adult brain tumor
adult glioblastoma

Additional relevant MeSH terms:
Glioblastoma
Nervous System Neoplasms
Central Nervous System Neoplasms
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Nervous System Diseases
Temozolomide
Dacarbazine
O(6)-benzylguanine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors