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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00436436
• Collaborator: (none)
• Enrollment: 12
• Locations: 2
• Arm: 1
• Actual Duration (Months): 41
• Patients Per Site: 6
• Patients Per Site Per Month: 0.1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors	Drug: O6-benzylguanine; Drug: temozolomide	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• 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
• Actual Study Start Date: Nov 13, 2006
• Actual Primary Completion Date: Mar 15, 2010
• Actual Study Completion Date: Apr 14, 2010

Arms and Interventions

Arm	Intervention/Treatment
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 Names: 06-BG ; Drug: temozolomide; Other Names: Temodar

Outcome Measures

Primary Outcome Measures

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

1. Objective Tumor Response Rate in Patients With Methylguanine Methyltransferase (MGMT)-Negative Tumors as Assessed by Immunohistochemistry (IHC) [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).

2. Toxicity as Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v 3) [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.

3. Best Overall Response [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

4. Progression-free Survival [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

5. Overall Survival [up to 2 years]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office	Bethesda	Maryland	United States	20892-1182
2	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mark Gilbert, M.D., Branch Chief, Neuro-Oncology Branch, National Institutes of Health Clinical Center (CC)
• ClinicalTrials.gov Identifier: NCT00436436
• Other Study ID Numbers: 070052; NCI-07-C-0052; AOI-NCI-07-C-0052; CDR0000529875
• First Posted: Feb 19, 2007
• Last Update Posted: Mar 28, 2017
• Last Verified: Feb 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• 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., Branch Chief, Neuro-Oncology Branch, 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; Temozolomide; O(6)-benzylguanine

Study Results

Participant Flow

Arm/Group Title	O6-benzylguanine & Temozolomide in Glioblastoma
Arm/Group 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. O6-benzylguanine temozolomide
Period Title: Overall Study
STARTED	12
COMPLETED	0
NOT COMPLETED	12

Baseline Characteristics

Arm/Group Title	O6-benzylguanine & Temozolomide in Glioblastoma
Arm/Group 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. O6-benzylguanine temozolomide
Overall Participants	12
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	10 83.3%
>=65 years	2 16.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.03 (9.64)
Sex: Female, Male (Count of Participants)
Female	1 8.3%
Male	11 91.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	10 83.3%
Unknown or Not Reported	2 16.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 8.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 16.7%
White	9 75%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	12 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

No analysis was performed. The study was closed to accrual after the company chose to stop the development of the drug.

Arm/Group Title	O6-benzylguanine & Temozolomide in Glioblastoma
Arm/Group 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. O6-benzylguanine temozolomide
Measure Participants	0

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Twelve patients were enrolled. The principal investigator wished to analyze the data but felt that there was insufficient data to report on and therefore closed the protocol when he left the National Cancer Institute (NCI).

Arm/Group Title	O6-benzylguanine & Temozolomide in Glioblastoma
Arm/Group 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. O6-benzylguanine temozolomide
Measure Participants	0

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	O6-benzylguanine & Temozolomide in Glioblastoma
Arm/Group 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. O6-benzylguanine temozolomide
Measure Participants	12
Count of Participants [Participants]	12 100%

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

No analysis was performed. The study was closed to accrual after the company chose to stop the development of the drug.

Arm/Group Title	O6-benzylguanine & Temozolomide in Glioblastoma
Arm/Group 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. O6-benzylguanine temozolomide
Measure Participants	0

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

No analysis was performed. The study was closed to accrual after the company chose to stop the development of the drug.

Arm/Group Title	O6-benzylguanine & Temozolomide in Glioblastoma
Arm/Group 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. O6-benzylguanine temozolomide
Measure Participants	0

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

No analysis was performed. The study was closed to accrual after the company chose to stop the development of the drug.

Arm/Group Title	O6-benzylguanine & Temozolomide in Glioblastoma
Arm/Group 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. O6-benzylguanine temozolomide
Measure Participants	0

Adverse Events

Time Frame	18 months and 4 days
Arm/Group Title	O6-benzylguanine & Temozolomide in Glioblastoma
Arm/Group 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. O6-benzylguanine temozolomide
All Cause Mortality
	O6-benzylguanine & Temozolomide in Glioblastoma
	Affected / at Risk (%)	# Events
Total	6/12 (50%)
Serious Adverse Events
	O6-benzylguanine & Temozolomide in Glioblastoma
	Affected / at Risk (%)	# Events
Total	8/12 (66.7%)
Blood and lymphatic system disorders
Leukocytes (total WBC)	4/12 (33.3%)	6
Lymphopenia	2/12 (16.7%)	5
Neutrophils/granulocytes (ANC/AGC)	2/12 (16.7%)	3
Platelets	3/12 (25%)	7
General disorders
Hypothermia	1/12 (8.3%)	1
Death due to progressive disease	6/12 (50%)	6
Metabolism and nutrition disorders
ALT, SGPT (serum glutamic pyruvic transaminase)	2/12 (16.7%)	3
AST, SGOT(serum glutamic oxaloacetic transaminase)	1/12 (8.3%)	1
Potassium, serum-high (hyperkalemia)	1/12 (8.3%)	1
Musculoskeletal and connective tissue disorders
Muscle weakness, generalized or specific area (not due to neuropathy)::Left-sided	1/12 (8.3%)	1
Nervous system disorders
Seizure	4/12 (33.3%)	6
Vascular disorders
Thrombosis/thrombus/embolism	1/12 (8.3%)	1
Other (Not Including Serious) Adverse Events
	O6-benzylguanine & Temozolomide in Glioblastoma
	Affected / at Risk (%)	# Events
Total	9/12 (75%)
Blood and lymphatic system disorders
Blood/Bone Marrow - Other (Specify, leukopenia)	1/12 (8.3%)	1
Edema: limb	1/12 (8.3%)	1
Hemoglobin	1/12 (8.3%)	1
Leukocytes (total WBC)	5/12 (41.7%)	7
Lymphopenia	4/12 (33.3%)	5
Neutrophils/granulocytes (ANC/AGC)	5/12 (41.7%)	8
Platelets	4/12 (33.3%)	8
Endocrine disorders
Cushingoid appearance (e.g., moon face, buffalo hump, centripetal obesity, cutaneous striae)	2/12 (16.7%)	2
Gastrointestinal disorders
Mucositis/stomatitis (clinical exam)::Oral cavity	1/12 (8.3%)	1
Vomiting	1/12 (8.3%)	1
Metabolism and nutrition disorders
ALT, SGPT (serum glutamic pyruvic transaminase)	3/12 (25%)	4
AST, SGOT(serum glutamic oxaloacetic transaminase)	2/12 (16.7%)	2
Bilirubin (hyperbilirubinemia)	1/12 (8.3%)	1
Magnesium, serum-high (hypermagnesemia)	1/12 (8.3%)	1
Sodium, serum-high (hypernatremia)	1/12 (8.3%)	1
Nervous system disorders
Confusion	1/12 (8.3%)	1
Skin and subcutaneous tissue disorders
Hair loss/alopecia (scalp or body)	1/12 (8.3%)	1

Limitations/Caveats

Dr. Howard A. Fine is no longer with the National Cancer Institute (NCI). For historical reasons, he is listed as the (original principal investigator) study official for this study.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.