Brain and Central Nervous System Tumors
Conditions
Keywords
recurrent childhood brain stem glioma, recurrent childhood brain tumor
Brief summary
This phase II trial is studying how well giving O6-benzylguanine together with temozolomide works in treating young patients with recurrent or progressive gliomas or brain stem tumors. Drugs used in chemotherapy, such as O6-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. O6-benzylguanine may help temozolomide work better by making tumor cells more sensitive to the drug. Giving more than one drug (combination chemotherapy) may kill more tumor cells.
Detailed description
PRIMARY OBJECTIVES: I. Determine the sustained objective response rate to the combination of O6-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brain stem tumors. SECONDARY OBJECTIVES: I. Determine the toxicity of this regimen in these patients. OUTLINE: This is a multicenter study. Patients are stratified according to tumor type (high-grade gliomas vs brain stem tumors). Patients receive O6-benzylguanine IV over 1 hour followed by oral temozolomide on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed to the earliest of 30 days following discontinuation of therapy or the initiation of additional anti-cancer therapy or death. PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.
Interventions
DRUGO6-benzylguanine
Dosing is based on the body surface area (BSA) calculated at the beginning of each course of therapy. O6-Benzylguanine, 120 mg/m\^2, will be administered as a one-hour intravenous (IV) infusion, daily for 5 days. Four consecutive weeks will constitute one course. Courses will be repeated every 4 weeks for up to 12 courses of therapy.
DRUGtemozolomide
Dosing is based on the body surface area (BSA) calculated at the beginning of each course of therapy. Temozolomide, 75 mg/m\^2 (rounded to the nearest 5 mg, the size of the smallest capsule) will be given orally, 30 minutes following the completion of each infusion of O6-Benzylguanine. Four consecutive weeks will constitute one course. Courses will be repeated every 4 weeks for up to 12 courses.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
* Tumor: Participants must have a high-grade glioma (including e.g. histologically confirmed anaplastic astrocytoma, glioblastoma multiforme, anaplastic oligodendroglioma, anaplastic ganglioma, gliosarcoma) or a brainstem tumor (histologic confirmation waived) with documentation of disease recurrence or progression after treatment with standard therapy. Participants must have bi-dimensionally measurable disease, defined as at least 1 lesion that can be measured in ≥ 2 dimensions * Age: 21 years of age or less * Performance status: Karnofsky 60-100% (for patients \> 16 years of age) or Lansky 60-100% (for patients ≤ 16 years of age) * Life expectancy: Not specified * Hematopoietic: Must have adequate bone marrow function defined as absolute neutrophil count \> 1,500/mm\^3, platelet count \> 100,000/mm\^3 (unsupported), hemoglobin \> 8 g/dL (may be supported), and absolute lymphocyte count ≥ 500/mm\^3 * Hepatic: Must have SGOT and SGPT ≤ 2.5 times upper limit of normal (ULN), bilirubin ≤ 1.5 times ULN, and no overt hepatic disease * Renal: Participants must have creatinine clearance ≥ 60 mL/min or creatinine based on age as follows: no greater than 0.8 mg/dL (for patients ≤ 5 years of age), no greater than 1.0 mg/dL (for patients 6 to 10 years of age), no greater than 1.2 mg/dL (for patients 11 to 15 years of age), or no greater than 1.5 mg/dL (for patients \> 15 years of age). There must be no overt renal disease * Cardiovascular: Must have no overt cardiac disease * Pulmonary: Must have no overt pulmonary disease * Other: Female participants of childbearing potential must have a negative pregnancy test prior to study registration, and must avoid breast-feeding. Female and male participants of childbearing or child-fathering potential must use effective contraception * Bone Marrow Transplant: Must be at least 6 months since prior allogeneic bone marrow transplantation and at least 3 months since prior autologous bone marrow or stem cell transplantation * Growth Factors: Must be at least 2 weeks since prior colony-stimulating factors (e.g., filgrastim \[G-CSF\], sargramostim \[GM-CSF\], or erythropoietin) * Prior Chemotherapy: Must have received last dose of myelosuppressive anticancer chemotherapy ≥ 3 weeks prior to study registration and ≥ 6 weeks for nitrosoureas. Must have received last dose of nonmyelosuppressive investigational agents or anticancer drugs ≥ 7 days prior to study registration. Participants who have received prior temozolomide are eligible * Concurrent Endocrine Therapy: Concurrent corticosteroid therapy is allowed * Prior Radiotherapy: Must have received last fraction of craniospinal irradiation and local irradiation to the primary tumor ≥ 12 weeks prior to study registration * Prior Therapy-Other: Must have recovered from all prior therapy
Exclusion criteria
* Must not have history of severe toxicity (≥ grade 3) associated with temozolomide * Must not be receiving other concurrent anticancer or investigational therapy * Must not have history of hypersensitivity to dacarbazine, temozolomide, or polyethylene glycol (PEG) * Must not have uncontrolled significant systemic illness including infection, or overt renal, hepatic, cardiac, or pulmonary disease * Must not be HIV positive
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With an Objective Response (Complete Response or Partial Response) | Week 8, 16, 24, 32, and 40 after starting therapy | The primary endpoint is to assess the percentage of participants with a sustained objective response (complete response (CR) or partial response (PR)). Response is assessed by magnetic resonance imaging (MRI) per the following criteria: CR - disappearance of tumor and PR - ≥50% reduction in tumor based on the maximal cross-sectional measurements. The response must be sustained for at least 8 weeks, and the date of the confirmed sustained response is the date at which the response was first noted by MRI. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Grade 3 or 4 Adverse Events at Least Possibly Related to the Combination of O6-benzylguanine and Temozolomide | From day 1 of therapy up to 49 months | Clinical and laboratory studies to assess adverse events are obtained at least every four weeks (prior to each course) with some laboratory studies obtained every 2 weeks. Adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0). Attribution of each adverse event to the treatment regimen is determined by the participant's attending physician at the enrolling institution and verified by the study chair. |
Countries
United States
Participant flow
Recruitment details
Participants from PBTC member institutions were enrolled between October 2005 and February 2008.
Participants by arm
| Arm | Count |
|---|---|
| Recurrent High-Grade Gliomas Participants with recurrent or progressive high-grade gliomas receive 120 mg/m\^2 of O6-Benzylguanine administered as a one-hour intravenous infusion, daily for 5 days. Temozolomide, 75 mg/m\^2 is administered orally, 30 minutes following the completion of each infusion of O6-Benzylguanine. Four consecutive weeks will constitute one course, and courses will be repeated every 4 weeks. | 25 |
| Recurrent Brain Stem Tumors Participants with recurrent or progressive brain stem tumors receive 120 mg/m\^2 of O6-Benzylguanine administered as a one-hour intravenous infusion, daily for 5 days. Temozolomide, 75 mg/m\^2 is administered orally, 30 minutes following the completion of each infusion of O6-Benzylguanine. Four consecutive weeks will constitute one course, and courses will be repeated every 4 weeks. | 16 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Disease progression | 21 | 15 |
Baseline characteristics
| Characteristic | Recurrent Brain Stem Tumors | Recurrent High-Grade Gliomas | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 16 Participants | 23 Participants | 39 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 2 Participants | 2 Participants |
| Age, Continuous | 7.8 years STANDARD_DEVIATION 3.9 | 13.4 years STANDARD_DEVIATION 5.1 | 11.2 years STANDARD_DEVIATION 5.4 |
| Region of Enrollment United States | 16 participants | 25 participants | 41 participants |
| Sex: Female, Male Female | 12 Participants | 9 Participants | 21 Participants |
| Sex: Female, Male Male | 4 Participants | 16 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 25 / 25 | 16 / 16 |
| serious Total, serious adverse events | 15 / 25 | 12 / 16 |
Outcome results
Primary
Percentage of Participants With an Objective Response (Complete Response or Partial Response)
The primary endpoint is to assess the percentage of participants with a sustained objective response (complete response (CR) or partial response (PR)). Response is assessed by magnetic resonance imaging (MRI) per the following criteria: CR - disappearance of tumor and PR - ≥50% reduction in tumor based on the maximal cross-sectional measurements. The response must be sustained for at least 8 weeks, and the date of the confirmed sustained response is the date at which the response was first noted by MRI.
Time frame: Week 8, 16, 24, 32, and 40 after starting therapy
Population: Participants included in assessing objective response were those who completed two courses of therapy or those who died or experienced progressive disease prior to completing the second course.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recurrent High-Grade Gliomas | Percentage of Participants With an Objective Response (Complete Response or Partial Response) | 4 Percent of Participants |
| Recurrent Brain Stem Tumors | Percentage of Participants With an Objective Response (Complete Response or Partial Response) | 0 Percent of Participants |
Secondary
Number of Patients With Grade 3 or 4 Adverse Events at Least Possibly Related to the Combination of O6-benzylguanine and Temozolomide
Clinical and laboratory studies to assess adverse events are obtained at least every four weeks (prior to each course) with some laboratory studies obtained every 2 weeks. Adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0). Attribution of each adverse event to the treatment regimen is determined by the participant's attending physician at the enrolling institution and verified by the study chair.
Time frame: From day 1 of therapy up to 49 months
Population: Participants who received at least one day of the treatment regimen were included in the analysis of this objective.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recurrent High-Grade Gliomas | Number of Patients With Grade 3 or 4 Adverse Events at Least Possibly Related to the Combination of O6-benzylguanine and Temozolomide | 16 Participants |
| Recurrent Brain Stem Tumors | Number of Patients With Grade 3 or 4 Adverse Events at Least Possibly Related to the Combination of O6-benzylguanine and Temozolomide | 10 Participants |