Brain and Central Nervous System Tumors
Conditions
Keywords
adult giant cell glioblastoma, adult gliosarcoma, recurrent adult brain tumor, adult glioblastoma
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.
Interventions
DRUGO6-benzylguanine
DRUGtemozolomide
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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. |
| 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 |
| 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 |
| Overall Survival | up to 2 years | Defined as the interval between the day of first administration of treatment and the date of death. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
O6-benzylguanine
temozolomide | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Death | 6 |
| Overall Study | Progression | 4 |
Baseline characteristics
| Characteristic | O6-benzylguanine & Temozolomide in Glioblastoma |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Age, Continuous | 52.03 years STANDARD_DEVIATION 9.64 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 12 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 12 |
| other Total, other adverse events | 9 / 12 |
| serious Total, serious adverse events | 8 / 12 |
Outcome results
Primary
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.
Time frame: 2-4 weeks
Population: No analysis was performed. The study was closed to accrual after the company chose to stop the development of the drug.
Secondary
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
Time frame: up to 2 years
Population: No analysis was performed. The study was closed to accrual after the company chose to stop the development of the drug.
Secondary
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).
Time frame: 2-4 weeks
Population: 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).
Secondary
Overall Survival
Defined as the interval between the day of first administration of treatment and the date of death.
Time frame: up to 2 years
Population: No analysis was performed. The study was closed to accrual after the company chose to stop the development of the drug.
Secondary
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
Time frame: up to 2 years
Population: No analysis was performed. The study was closed to accrual after the company chose to stop the development of the drug.
Secondary
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.
Time frame: 18 months and 4 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| O6-benzylguanine & Temozolomide in Glioblastoma | Toxicity as Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v 3) | 12 Participants |