OBJECTIVES:
- Determine the maximum tolerated dose of imatinib mesylate in patients with recurrent oligodendroglioma or mixed oligoastrocytoma who are currently on enzyme-inducing anticonvulsant therapy. (Phase I)
- Determine the efficacy of imatinib mesylate, as measured by response, survival, and progression-free survival, in patients with recurrent oligodendroglioma or mixed oligoastrocytoma. (Phase II)
- Compare pilot data of patients who have undergone > 2 prior chemotherapy regimens for recurrent, progressive, or mixed oligodendroglioma with traditional patients with recurrent or mixed oligodendroglioma. (Phase II and pilot study)
- Determine the toxicity and safety of this drug in these patients. (Phases I, II, and pilot study)
- Correlate, preliminarily, 1p/19q alterations, alpha-PDFGR gene amplification, and levels of related downstream signaling elements in tumor tissue with clinical response in patients treated with this drug. (Phases I, II, and pilot study)
OUTLINE: This is a multicenter, phase I, dose-escalation study followed by a phase II and a pilot study.
- Phase I: Patients receive oral imatinib mesylate twice daily for 4 weeks. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
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 preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
- Phase II:
- Group 1 (concurrent enzyme-inducing anticonvulsants [EIACs]): Patients receive oral imatinib mesylate, at the MTD determined in phase I, twice daily for 4 weeks.
- Group 2 (non EIACs): Patients receive oral standard-dose imatinib mesylate twice daily for 4 weeks.
In both groups, treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity.
- Pilot study: Patients are stratified and assigned to treatment groups as in phase II. Patients receive oral imatinib as in phase II.
Patients are followed every 2 months.
PROJECTED ACCRUAL: A total of 93 patients will be accrued to this study.
DISEASE CHARACTERISTICS:
- Histologically confirmed oligodendroglioma or mixed oligoastrocytoma
- Grade 2-4
- Recurrent disease
- Patients with mixed gliomas must have > 25% oligodendrogliomatous component
- Failed prior surgery, radiotherapy, and temozolomide or nitrosourea-based therapy
- Progressive disease by MRI or CT scan
- Measurable or evaluable disease by MRI or CT scan
- More than 2 prior chemotherapy regimens for progressive or recurrent disease (pilot study only)
- Currently taking anticonvulsants which can induce cytochrome p450 (e.g., phenytoin, carbamazepine, barbiturates, or primidone (Phase I only)
- No prior or concurrent significant intratumoral hemorrhage
PATIENT CHARACTERISTICS:
Age
- 18 and over
Performance status
- ECOG 0-2
Life expectancy
- Not specified
Hematopoietic
- Absolute neutrophil count at least 1,500/mm^3
- Platelet count at least 100,000/mm^3
- Hemoglobin at least 9 g/dL
Hepatic
- Bilirubin no greater than 1.5 mg/dL
- AST no greater than 3 times upper limit of normal
Renal
- Creatinine no greater than 2.0 mg/dL
Cardiovascular
- No myocardial infarction within the past 6 months
- No congestive heart failure requiring maintenance therapy for life-threatening ventricular arrhythmias
- No New York Heart Association class III or IV heart disease
Other
- No active uncontrolled infection
- No other severe concurrent disease that would preclude study or interfere significantly with interpreting potential drug-induced toxic effects
- No other active malignancy except nonmelanoma skin cancer
- No concurrent serious immunocompromised status unless related to concurrent steroids
- HIV-positive patients allowed
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for 6 months after study participation
PRIOR CONCURRENT THERAPY:
Biologic therapy
- At least 2 weeks since prior biologic noncytotoxic agents (e.g., thalidomide or interferon)
- No concurrent biologic therapy or immunotherapy for brain cancer
Chemotherapy
- See Disease Characteristics
- No prior interstitial chemotherapy, including carmustine wafers, unless separate lesion seen on MRI outside of prior treatment field
- At least 2 weeks since prior vincristine
- At least 4 weeks since other prior chemotherapy (6 weeks for nitrosoureas)
- No concurrent chemotherapy for brain cancer
Endocrine therapy
- At least 2 weeks since prior tamoxifen
- Concurrent corticosteroids allowed if dose stable for at least 1 week prior to study entry
- No concurrent hormonal therapy for brain cancer
Radiotherapy
- See Disease Characteristics
- At least 12 weeks since prior radiotherapy
- No prior stereotactic radiosurgery or interstitial brachytherapy unless separate lesion seen on MRI outside of prior treatment field
- No concurrent radiotherapy for brain cancer
Surgery
- See Disease Characteristics
- At least 2 weeks since prior surgery for initial or progressive disease and recovered
- No concurrent surgery for brain cancer
Other
- At least 2 weeks since prior isotretinoin
- At least 4 weeks since prior investigational agents
- No concurrent therapeutic warfarin or heparin
- Low-dose warfarin and heparin (1 mg daily) allowed
- No other concurrent investigational or noninvestigational therapy for brain cancer
Last updated: 03/26/2012
NCT ID: NCT00049127
IRB Number:1433-02
Find Mayo Clinic on