Anaplastic Astrocytoma, Central Nervous System Neoplasm, Glioblastoma, Gliosarcoma, Spinal Cord Neoplasm
Conditions
Brief summary
This phase II trial is studying how well giving radiation therapy together with temozolomide and lomustine works in treating young patients with newly diagnosed gliomas. Radiation therapy uses high energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide and lomustine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy together with temozolomide and lomustine after surgery may kill any remaining tumor cells.
Detailed description
PRIMARY OBJECTIVES: I. Compare event-free survival of pediatric patients with newly diagnosed high-grade gliomas treated with adjuvant radiotherapy and temozolomide followed by temozolomide and lomustine with historical controls. II. Determine the toxicity of this regimen in these patients. III. Correlate MGMT and p53 expression in tumor tissue with outcome in patients treated with this regimen. IV. Correlate polymorphisms in GSTP1, GSTM1 and GSTT1 genes and GSTP1 protein expression in tumors with survival in patients treated with this regimen. OUTLINE: This is a pilot, multicenter study. CHEMORADIOTHERAPY: Patients receive oral temozolomide once daily on days 1-42. Patients also undergo concurrent radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33 and 36-40. Patients who did not undergo prior gross total resection also undergo boost radiotherapy once daily on days 43-47. MAINTENANCE CHEMOTHERAPY: Four weeks after completion of chemoradiotherapy, patients receive oral temozolomide once daily on days 1-5 and oral lomustine on day 1. Treatment repeats every 42 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 1 year, every 6 months for 3 years and then annually thereafter.
Interventions
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGLomustine
Given PO
RADIATIONRadiation Therapy
Undergo radiation therapy
DRUGTemozolomide
Given PO
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed, newly diagnosed high-grade glioma of 1 of the following histologies: * Anaplastic astrocytoma * Glioblastoma multiforme * Gliosarcoma * Primary spinal cord malignant gliomas allowed * No primary brainstem tumors * Has undergone surgical resection or biopsy of the tumor within the past 31 days * Pre-operative and post-operative brain MRI with and without gadolinium-contrast OR pre-operative and post-operative spine MRI for spinal cord primaries * Post-operative MRI not required for patients who undergo biopsy only * No evidence of neuraxis dissemination * Spine MRI and cerebrospinal fluid cytology required only if clinically indicated * Performance status - Karnofsky 50-100% (for patients \> 16 years of age) * Performance status - Lansky 50-100% (for patients ≤ 16 years of age) * At least 8 weeks * Absolute neutrophil count ≥ 1,000/mm\^3 * Platelet count ≥ 100,000/mm\^3 (transfusion independent) * Hemoglobin ≥ 8 g/dL (transfusions allowed) * Bilirubin ≤ 1.5 times upper limit of normal (ULN) * ALT ≤ 2.5 times ULN * Albumin ≥ 2 g/dL * Creatinine ≤ 1.5 times ULN * Creatinine clearance or radioisotope glomerular filtration rate ≥ lower limit of normal * No evidence of dyspnea at rest * No exercise intolerance * Pulse oximetry ≥ 94% (if determination is clinically indicated) * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for 2 months after study participation * Able to swallow oral medication * Seizures allowed provided they are well controlled with anticonvulsants * No hypersensitivity to temozolomide * No prior biologic agents * No prior chemotherapy * Prior corticosteroids allowed * No concurrent corticosteroids as an antiemetic * Concurrent corticosteroids allowed only for treatment of increased intracranial pressure * No concurrent radiotherapy using cobalt-60 * See Disease Characteristics * No other prior treatment * No concurrent phenobarbital or cimetidine * No concurrent co-trimoxazole for Pneumocystis carinii pneumonia prophylaxis during study chemoradiotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| One Year Overall Survival | One year | Estimated one year survival using the Kaplan-Meier methodology. |
| Occurrence of Death Attributable to Complications of Protocol Therapy | While receiving protocol therapy (up to 301 days excluding delays) or within 30 days of Termination of Protocol Therapy | Number of deaths due to complications of protocol therapy. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Surgery, Chemoradiotherapy, Rest, Maintenance, FUP Patients must begin therapy within 31 days of surgery. Chemoradiotherapy = Radiation Therapy Dose: 54.0 Gy with a Boost of 5.4 Gy Temozolomide 90mg/m2/day daily for 42 days. Maintenance consists of 6 treatment cycles of combo chemotherapy with lomustine and temozolomide. Maintenance will begin 4 weeks following radiation. Five days of temozolomide (day 1 - 5) and one dose of lomustine (day 1) followed by 36 days of rest = 1 treatment cycle.
lomustine: Capsule
temozolomide: Capsule
adjuvant therapy
radiation therapy | 118 |
| Total | 118 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 9 |
| Overall Study | Death | 1 |
| Overall Study | Ineligible | 12 |
| Overall Study | Lack of Efficacy | 47 |
| Overall Study | Physician Decision | 5 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Surgery, Chemoradiotherapy, Rest, Maintenance, FUP |
|---|---|
| Age, Categorical <=18 years | 110 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Age, Continuous | 12 years |
| Region of Enrollment Australia | 4 participants |
| Region of Enrollment Canada | 15 participants |
| Region of Enrollment New Zealand | 1 participants |
| Region of Enrollment United States | 98 participants |
| Sex: Female, Male Female | 55 Participants |
| Sex: Female, Male Male | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 83 / 106 |
| serious Total, serious adverse events | 3 / 106 |
Outcome results
Primary
Occurrence of Death Attributable to Complications of Protocol Therapy
Number of deaths due to complications of protocol therapy.
Time frame: While receiving protocol therapy (up to 301 days excluding delays) or within 30 days of Termination of Protocol Therapy
Population: 106 eligible patients out of 118 patients enrolled is the population basis for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Surgery, Chemoradiotherapy, Rest, Maintenance, FUP | Occurrence of Death Attributable to Complications of Protocol Therapy | 1 patients |
Primary
One Year Overall Survival
Estimated one year survival using the Kaplan-Meier methodology.
Time frame: One year
Population: Population is based on 106 eligible patients out of 118 patients enrolled.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Surgery, Chemoradiotherapy, Rest, Maintenance, FUP | One Year Overall Survival | 0.7208 Estimated probability |