Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II, Phase I	Treatment	Completed	3 to 21	NCI	PBTC-006 NCT00021229

Objectives

Primary

1. Determine the maximum tolerated dose of imatinib mesylate with or without radiotherapy in children with newly diagnosed poor prognosis brainstem glioma or recurrent high-grade intracranial glioma stratified according to the use of enzyme-inducing anticonvulsant drugs (EIACDs). (Phase I) (Phase I, strata I and IIA closed to accrual as of 5/10/04.)
2. Determine the safety and efficacy of this drug in patients with diffuse intrinsic brainstem gliomas. (Phase II)

Secondary

1. Determine the therapeutic activity of this regimen in these patients. (Phase II)
2. Determine the pharmacokinetics of these regimens in these patients. (Phase I) (Phase I, strata I and IIA closed to accrual as of 5/10/04.)
3. Compare the effects of EIACD use in these patients when treated with this drug. (Phase I) (Phase I, strata I and IIA closed to accrual as of 5/10/04.)
4. Determine the progression-free survival and overall survival of patients treated with this drug. (Phase II)

Entry Criteria

Disease Characteristics:

• Stratum I:
  • Newly diagnosed diffuse intrinsic brainstem malignant glioma
  • No disseminated disease
  • No radiographic evidence of intratumoral hemorrhage before or after radiotherapy



• Stratum II (A- no concurrent enzyme-inducing anticonvulsant drugs [EIACDs] vs B-concurrent use of EIACDs [closed to accrual as of 5/10/04]):
  • 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

Prior/Concurrent Therapy:

Biologic therapy:

• More than 2 weeks since prior colony-stimulating growth factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF], or epoetin alfa)
• At least 3 months since prior bone marrow transplantation (stratum II)

Chemotherapy:

• No prior chemotherapy (stratum I)
• At least 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas) and recovered (stratum II)

Endocrine therapy:

• Prior routine corticosteroids allowed
• Concurrent corticosteroids allowed if on stable or decreasing dose for at least 1 week prior to study

Radiotherapy:

• Stratum I:
  • No prior radiotherapy
• Stratum II:
  • 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 metastases

Surgery:

• See Disease Characteristics

Other:

• No prior imatinib mesylate (stratum II)
• At least 2 weeks since beginning or discontinuing medications affecting cytochrome P450 3A4, 5, and 7 isoenzyme metabolism
• No other concurrent anticancer drug
• No other concurrent experimental drug
• No concurrent warfarin
• No concurrent enzyme-inducing anticonvulsant drugs (stratum I)

Patient Characteristics:

Age:

• 3 to 21

Performance status:

• Karnofsky 50-100%

  OR

• Lansky 50-100%

Life expectancy:

• Not specified

Hematopoietic:

• 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)

Hepatic:

• Bilirubin no greater than 1.5 times normal for age
• SGPT less than 3 times normal for age
• Albumin at least 2 g/dL
• No significant hepatic disease

Renal:

• Creatinine less than 1.5 times normal for age

  OR

• Glomerular filtration rate greater than 70 mL/min
• No significant renal disease

Cardiovascular:

• No significant cardiac disease
• No deep venous or arterial thrombosis within the past 6 weeks

Pulmonary:

• No significant pulmonary disease

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception during and for 6 months after study participation
• No uncontrolled infection
• No significant gastrointestinal disease
• No significant psychiatric disease
• Neurological deficits allowed if stable for at least 1 week prior to study (stratum II)

Expected Enrollment

Approximately 140 patients will be accrued for this study within 2 years.

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 two 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 2-3 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 5/10/04.)
  
  
  
  • Stratum II A (recurrent or refractory high-grade intracranial gliomas/no concurrent EIACs): Patients receive imatinib mesylate as in stratum I. (Closed to accrual as of 5/10/04).
  
  
  
  • Stratum II B (recurrent or refractory high-grade intracranial gliomas and concurrent EIACs): Patients receive imatinib mesylate as in stratum I.
  
  
  

Cohorts of 3-6 patients receive escalating doses of imatinib mesylate until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which at least 5 of 6 patients experience no dose-limiting toxicity.

• Phase II: (Open to accrual as of 5/10/04.)
  • Stratum I only: Patients undergo radiotherapy as in phase I. Patients receive imatinib mesylate at the MTD established in phase I.

Patients are followed every 3 months for 1 year, every 6 months for 4 years, and then annually thereafter.

Williams G, Fahey FH, Treves ST, et al.: Exploratory evaluation of two-dimensional and three-dimensional methods of FDG PET quantification in pediatric anaplastic astrocytoma: a report from the Pediatric Brain Tumor Consortium (PBTC). Eur J Nucl Med Mol Imaging 35 (9): 1651-8, 2008.[PUBMED Abstract]

Pollack IF, Jakacki RI, Blaney SM, et al.: Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: a Pediatric Brain Tumor Consortium report. Neuro Oncol 9 (2): 145-60, 2007.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Pediatric Brain Tumor Consortium

Ian Pollack, MD, Protocol chair		Ph: 412-692-5881

Registry Information
Official Title		A Phase I/II Trial Of STI571 In Children With Newly Diagnosed Poor Prognosis Brainstem Gliomas And Recurrent Intracranial Malignant Gliomas
Trial Start Date		2001-05-17
Trial Completion Date		2008-08-14
Registered in ClinicalTrials.gov		NCT00021229
Date Submitted to PDQ		2001-05-24
Information Last Verified		2005-05-11
NCI Grant/Contract Number		CA81457

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