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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

Primary Purpose

Brain and Central Nervous System Tumors

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
O6-benzylguanine
temozolomide
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Brain and Central Nervous System Tumors focused on measuring adult giant cell glioblastoma, adult gliosarcoma, recurrent adult brain tumor, adult glioblastoma

Eligibility Criteria

18 Years - 120 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
  • NCI - Neuro-Oncology Branch

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

O6-benzylguanine & Temozolomide in Glioblastoma

Arm Description

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.

Outcomes

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

Full Information

First Posted
February 15, 2007
Last Updated
February 7, 2017
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00436436
Brief Title
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

2. Study Status

Record Verification Date
February 2017
Overall Recruitment Status
Terminated
Why Stopped
Study closed to accrual after the company chose to stop development of the drug.
Study Start Date
November 13, 2006 (Actual)
Primary Completion Date
March 15, 2010 (Actual)
Study Completion Date
April 14, 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Brain and Central Nervous System Tumors
Keywords
adult giant cell glioblastoma, adult gliosarcoma, recurrent adult brain tumor, adult glioblastoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Actual)

8. Arms, Groups, and Interventions

Arm Title
O6-benzylguanine & Temozolomide in Glioblastoma
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
O6-benzylguanine
Other Intervention Name(s)
06-BG
Intervention Type
Drug
Intervention Name(s)
temozolomide
Other Intervention Name(s)
Temodar
Primary Outcome Measure Information:
Title
Confirmed Best Objective Tumor Response Rate (Complete or Partial Response) in Patients With Methylguanine Methyltransferase (MGMT)-Positive Tumors as Assessed by Immunohistochemistry (IHC)
Description
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.
Time Frame
2-4 weeks
Secondary Outcome Measure Information:
Title
Objective Tumor Response Rate in Patients With Methylguanine Methyltransferase (MGMT)-Negative Tumors as Assessed by Immunohistochemistry (IHC)
Description
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
Title
Toxicity as Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v 3)
Description
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
Title
Best Overall Response
Description
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
Title
Progression-free Survival
Description
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
Title
Overall Survival
Description
Defined as the interval between the day of first administration of treatment and the date of death.
Time Frame
up to 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
120 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Howard A Fine, M.D.
Organizational Affiliation
NCI - Neuro-Oncology Branch
Official's Role
Principal Investigator
Facility Information:
Facility Name
Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892-1182
Country
United States
Facility Name
NCI - Neuro-Oncology Branch
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892-8200
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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