Imatinib Mesylate With or Without Radiation Therapy in Treating Young Patients With Newly Diagnosed or Recurrent Glioma

Study Overview
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Brief Summary
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Phase I/II trial to estimate the maximum tolerated dose of imatinib mesylate in newly diagnosed brain stem gliomas and recurrent high grade gliomas and to assess the effectiveness of imatinib mesylate in treating young patients who have newly diagnosed intrinsic brain stem glioma. Imatinib mesylate may interfere with the growth of tumor cells by blocking the enzymes necessary for their growth. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining imatinib mesylate with radiation therapy may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose (MTD) of imatinib mesylate after completion of radiation in children with newly diagnosed poor prognosis brainstem gliomas. (Phase I, strata I closed to accrual as of 5/28/04.) II. Determine the maximum tolerated dose (MTD) of imatinib mesylate in children with recurrent high-grade intracranial glioma stratified according to the use of enzyme-inducing anticonvulsant drugs (EIACDs). (Phase I, strata IIA and IIB closed to accrual as of 8/15/03 and 8/15/04, respectively) III. Determine the safety and efficacy of this drug in patients with newly diagnosed diffuse intrinsic brainstem gliomas. (Phase II) SECONDARY OBJECTIVES: I. Explore neuroimaging and biological correlatives of therapeutic activity of this regimen in these patients. (Phase I, all strata closed to accrual as of 8/15/04) II. Determine the pharmacokinetics of these regimens in these patients overall and by enzyme-inducing anticonvulsant drugs (EIACDs) (Phase I, all strata closed to accrual as of 8/15/04.) III. Estimate the progression-free survival (PFS) and overall survival (OS) of newly diagnosed diffuse intrinsic brainstem gliomas treated with this drug. (Phase I and II) OUTLINE: This is a phase I dose-escalation, multicenter study followed by a phase II. Patients are stratified according to tumor type (newly diagnosed intrinsic brainstem glioma vs recurrent/refractory intracranial high-grade glioma). Patients in stratum II (phase I only) are further stratified according to concurrent use of enzyme-inducing anticonvulsant drugs (EIACDs) (yes vs no). Patients are assigned to one of three strata in the phase I study. Phase I Stratum I (newly diagnosed brainstem glioma): Patients undergo radiotherapy once daily five days a week for 6 weeks. Beginning 1-3 weeks after completion of radiotherapy, patients without evidence of intratumoral bleed receive oral imatinib mesylate twice daily. Imatinib mesylate treatment repeats every 4 weeks for up to 13 courses in the absence of disease progression or unacceptable toxicity. (Closed to accrual as of 5/28/04.) Stratum II A (recurrent or refractory high-grade intracranial gliomas/no concurrent EIACDs): Patients receive imatinib mesylate as in stratum I. (Closed to accrual as of 8/15/03.) Stratum II B (recurrent or refractory high-grade intracranial gliomas and concurrent EIACDs): Patients receive imatinib mesylate as in stratum I. (Closed to accrual as of 8/15/04.) Cohorts of 2-3 patients receive escalating doses of imatinib mesylate until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which it is estimated that 20% of patients will experience dose-limiting toxicity. MTDs are independently estimated in each strata. For stratum I, newly diagnosed brain stem gliomas, the dose level which at least 5 of 6 patients experience no dose-limiting toxicity will be the dose used in the efficacy and safety phase (phase II). Phase II: (Open to accrual as of 5/28/04.) Stratum I only: Patients undergo radiotherapy as in phase I. Patients receive imatinib mesylate at the MTD established in phase I. Patients enrolled in the phase I portion and not treated at the MTD are to be followed for the shortest of 1) three months after the last protocol based treatment or 2) the date other therapy is initiated. Stratum I patients treated at the MTD in the phase I portion and all patients in the phase II portion of the study are to be followed until death or withdrawal from the study PROJECTED ACCRUAL: Approximately 140 patients will be accrued for this study within 2 years.

Official Title
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A Phase I/II Trial Of STI571 In Children With Newly Diagnosed Poor Prognosis Brainstem Gliomas And Recurrent Intracranial Malignant Gliomas

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Drug: imatinib mesylate
* Radiation: local irradiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age 3 to 21 Performance status of Karnofsky 50-100% OR Lansky 50-100% Absolute neutrophil count greater than 1,000/mm3 Platelet count greater than 100,000/mm3 (transfusion independent) Hemoglobin greater than 8 g/dL (transfusion allowed) Bilirubin no greater than 1.5 times normal for age SGPT less than 3 times normal for age Albumin at least 2 g/dL Creatinine less than 1.5 times normal for age OR Glomerular filtration rate greater than 70 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective barrier contraception during and for 6 months after study participation Stratum I Newly diagnosed diffuse intrinsic brainstem malignant glioma No disseminated disease No radiographic evidence of intratumoral hemorrhage before or during radiotherapy No prior chemotherapy (beyond routine corticosteroids) No prior irradiation Must not be receiving enzyme-inducing anticonvulsant drugs Stratum II Histologically confirmed recurrent or refractory anaplastic astrocytoma, glioblastoma multiforme, or other high-grade glioma (including recurrent brain stem glioma No intratumoral hemorrhage unrelated to prior surgical procedure No myelosuppressive chemotherapy within 3 weeks (6 weeks if a nitrosourea agent) of study entry No prior imatinib mesylate At least 3 months since prior craniospinal radiotherapy (18 Gy or more) At least 8 weeks since prior local radiotherapy to primary tumor At least 2 weeks since prior focal radiotherapy for symptomatic At least 3 months since prior bone marrow transplantation Neurological deficits allowed if stable for at least 1 week prior to study Exclusion Criteria Receiving other anticancer or experimental drug therapy. Ongoing uncontrolled infection. Significant cardiac, hepatic, gastrointestinal, renal, pulmonary, or psychiatric disease. Deep venous or arterial thrombosis within 6 weeks of registration. Taking warfarin. Newly diagnosed diffuse intrinsic brainstem malignant glioma with disseminated disease (stratum I) Intratumoral hemorrhage

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imatinib mesylate<br> | Drug: imatinib mesylate<br>* Phase 1 Stratum I: Starting dose level of 350 mg/m2/day every 28 days X 13 courses (dose escalation) Phase I Stratum IIA: Starting dose level of 465 mg/m2/day every 28 days X 13 courses (dose escalation) Phase I Stratum IIB: Starting dose level of 465 mg/m2/day every 28 days X 13 courses (dose escalation) Phase II: Phase I Stratum I determined dose (Maximum tolerated dose) every 28 days X 13 courses.<br>Radiation: local irradiation therapy<br>* Phase I Stratum I: Total dose of 5580 cGy using conventional or conformal volume-based delivery techniques once daily, 5 days/week for six weeks prior to receiving imatinib. Phase II: Total dose of 5580 cGy using conventional or conformal volume-based delivery techniques once daily, 5 days/week for six weeks prior to receiving imatinib.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants in Phase I Stratum I With Dose Limiting Toxicities (DLT) Observed During First 8 Weeks (Courses 1 and 2) of Imatinib Therapy | The dose limiting toxicity (DLT) analysis population consists of phase I stratum I participants who developed DLT during the maximum tolerated dose (MTD) estimation period (course 1 and 2) or who completed the MTD estimation period (courses 1 and 2) without DLTs. DLTs observed during courses 1 and 2 were used to estimate the MTD. The estimated MTD based on the 23 participants who either had a DLT during course 1 or 2 or completed courses 1 and 2 without DLT is 265 mg/m2/day. | Day 1 of Imatinib Mesylate Therapy to Week 8 | 
| Number of Participants in Phase I Stratum II With Dose Limiting Toxicities (DLT) Observed During First 8 Weeks (Courses 1 and 2) of Imatinib Therapy | The dose limiting toxicity (DLT) analysis population consisted of phase I stratum II participants who developed DLT during the maximum tolerated dose (MTD) estimation period (courses 1 and 2) or who completed the MTD estimation period (courses 1 and 2) without DLTs. DLTs observed during courses 1 and 2 were used to estimate the MTD. The estimated MTD based on the DLT analysis population of 20 in stratum IIA was 465 mg/m2/day. An MTD was not established in stratum IIB as no DLTs were observed at the higher dose levels of 620 and 800 mg/m2/day. | Day 1 of Imatinib Mesylate Therapy to Week 8 | 
| Median Progression-free Survival (PFS) | Progression-free survival is defined as the interval from initiation of treatment to the earliest of disease progression (tumor increase of 25% over baseline tumor measurement; appearance of new lesion(s); or progressive/worsening neurological status) or death for patients who failed, or to the last date of follow up for patients without failure. | Assessed pre-radiation, before the first dose of imatinib, and then every 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Volume FLAIR at Two Weeks After Completion of Radiation | This study attempted to investigate in an exploratory manner the effect of radiation (RT) on changes in various neuroimaging variables in pediatric brainstem gliomas (stratum I). Neuroimaging changes may have some association with outcome (response, survival, etc.). Volume FLAIR is one parameter obtained from standard magnetic resonance imaging (MRI) studies of the brain. Volume FLAIR was obtained at baseline (pre-radiation) and within two (+/- one) weeks after completion of RT. | Baseline and two weeks post completion of radiation | 
| Peak Concentration (Cmax) | Peak concentration (cmax) is a pharmacokinetic measure defined as the highest concentration of a drug measured after the drug is administered. The cmax of imatinib mesylate on day 1 of course 1 is reported. Two milliliter (0.5 ml for children under the age of 5) blood samples were collected immediately prior to imatinib mesylate administration on Day 1 of Course 1 and at the following timepoints following drug administration: 0.5, 1, 1.5, 2, 4, 10 and 12 hours after the morning dose. | Day 1 of Course 1 | 
| Median Overall Survival | Overall Survival (OS) is defined as the interval from initiation of treatment to death or date of last contact for surviving patients. | Assessed before radiation therapy, before the first dose of imatinib, then every 8 weeks. | 
| Pre-treatment Basic Fibroblast Growth Factor Values From Urine | This study attempted to investigate in an exploratory manner the effect of biological markers on tumor growth. Basic fibroblast growth factor (bFGF) may play a role in tumor development by helping tumor vessels establish and grow. Urine was collected from participants before treatment to measure the baseline urine bFGF values. | Pre-treatment | 
| Pre-treatment Basic Fibroblast Growth Factor Values From Plasma | This study attempted to investigate in an exploratory manner the effect of biological markers on tumor growth. Basic fibroblast growth factor (bFGF) may play a role in tumor development by helping tumor vessels establish and grow. Blood (plasma) was drawn from participants before treatment to measure the baseline plasma bFGF values. | Pre-treatment | 
| Pre-treatment Vascular Endothelial Growth Factor From Urine | This study attempted to investigate in an exploratory manner the effect of biological markers on tumor growth. Vascular endothelial growth factor (VEGF) may play a role in tumor development by helping tumor vessels establish and grow. Urine was collected from participants before treatment to measure the baseline urine VEGF values. | Pre-treatment | 
| Pre-treatment Vascular Endothelial Growth Factor Values From Plasma | This study attempted to investigate in an exploratory manner the effect of biological markers on tumor growth. Vascular endothelial growth factor (VEGF) may play a role in tumor development by helping tumor vessels establish and grow. Blood (plasma) was drawn from participants before treatment to measure the baseline plasma VEGF values. | Pre-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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childhood central nervous system germ cell tumor, childhood high-grade cerebral astrocytoma, untreated childhood brain stem glioma, recurrent childhood brain stem glioma, recurrent childhood cerebral astrocytoma