temozolomide plus irinotecan in treating patients with recurrent malignant glioma

Conditions: Brain and Central Nervous System Tumors

Summary: rationale: drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. combining more than one drug may kill more tumor cells. purpose: phase i/ii trial to study the effectiveness of temozolomide plus irinotecan in treating patients who have recurrent malignant glioma.

objectives: * determine the maximum tolerated dose and dose-limiting toxicity of irinotecan when administered with temozolomide in patients with recurrent malignant glioma. * determine the safety profile of this regimen in this patient population. * determine the efficacy of this treatment regimen as measured by 6-month progression-free survival and objective tumor response in these patients. * characterize the pharmacokinetics of this treatment regimen in these patients. * determine the antitumor activity of this treatment regimen in these patients. outline: this is a multicenter, dose-escalation study of irinotecan. patients are stratified according to concurrent enzyme-inducing anti-epileptic drugs (eiaeds) (e.g., phenytoin, phenobarbital, carbamazepine, or primidone) (yes vs no). in phase i of the study, patients receive oral temozolomide on days 1-5 and irinotecan iv over 90 minutes on days 1 and 14. treatment continues every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. patients concurrently on eiaeds undergo dose escalation of irinotecan. cohorts of 3 to 6 patients receive escalating doses of irinotecan until the maximum tolerated dose (mtd) is determined. the mtd is defined as the dose preceding that at which 2 of 3 or 6 patients experience dose-limiting toxicity. in phase ii of the study, patients receive the same treatment as in phase i at the mtd. patients are followed every 2 months for 1 year, every 3 months for 1 year, every 4 months for 1 year, every 6 months until progression, and then every 4 months for survival. projected accrual: a total of 30 patients will be accrued for phase i within 10 months and 48 patients will be accrued for phase ii within 6-8 months.

Eligibility criteria:
disease characteristics: * histologically confirmed supratentorial malignant primary glioma of one of the following subtypes: * glioblastoma multiforme * anaplastic astrocytoma * anaplastic oligodendroglioma * mixed malignant glioma * original histology of low-grade glioma allowed if subsequent histological confirmation of malignant glioma * measurable recurrent or residual primary disease by mri * lesions with clearly defined margins * evidence of tumor recurrence or progression by mri or ct scan * confirmation of true progressive disease by pet or thallium scan, magnetic resonance spectroscopy, or surgical documentation after prior interstitial brachytherapy or stereotactic radiosurgery * no more than 3 relapses after prior chemotherapy/cytotoxic therapy (including polifeprosan 20 with carmustine implant) for phase i and no more than 2 relapses for phase ii patient characteristics: age: * 18 and over performance status: * karnofsky 60-100% life expectancy: * not specified hematopoietic: * wbc at least 3,000/mm\^3 * absolute neutrophil count at least 1,500/mm\^3 * platelet count at least 100,000/mm\^3 * hemoglobin at least 10 g/dl hepatic: * bilirubin no greater than 1.5 mg/dl * sgot no greater than 2 times upper limit of normal renal: * creatinine no greater than 1.5 mg/dl cardiovascular: * no uncontrolled hypertension, unstable angina, or symptomatic congestive heart failure * no myocardial infarction within the past 6 months * no serious uncontrolled cardiac arrhythmia other: * not pregnant or nursing * negative pregnancy test * fertile patients must use effective contraception * no mental incapacitation * hiv negative * no aids-related disease * no significant ongoing alcoholism or substance abuse * no severe nonmalignant systemic disease * no active infection * no other severe disease that would preclude study prior concurrent therapy: biologic therapy: * at least 1 week since prior interferon or thalidomide and recovered * no concurrent anticancer immunotherapy * no concurrent sargramostim (gm-csf) * no concurrent prophylactic filgrastim (g-csf) during first course of study therapy chemotherapy: * see disease characteristics * recovered from prior chemotherapy * at least 2 weeks since prior vincristine * at least 3 weeks since prior procarbazine * at least 4 weeks since prior cytotoxic chemotherapy (6 weeks for nitrosourea) * prior radiosensitizers allowed * no prior temozolomide or irinotecan * no other concurrent anticancer chemotherapy endocrine therapy: * at least 1 week since prior tamoxifen and recovered * no concurrent anticancer hormonal therapy * phase ii: * non-increasing dose of corticosteroids allowed radiotherapy: * see disease characteristics * at least 4 weeks since prior radiotherapy and recovered * no concurrent anticancer radiotherapy surgery: * see disease characteristics * at least 1-3 weeks since prior surgical resection and recovered other: * at least 1 week since prior noncytotoxic agents (e.g., isotretinoin) and recovered * concurrent enzyme-inducing anti-epileptic drugs with or without steroids allowed * no concurrent valproic acid as a single agent * no concurrent medication that would preclude study (e.g., nonsteroidal immunosuppressive agents) * no other concurrent investigational drugs * no concurrent participation in other clinical study

Keywords: recurrent adult brain tumor adult glioblastoma adult anaplastic astrocytoma adult anaplastic oligodendroglioma adult mixed glioma adult giant cell glioblastoma adult gliosarcoma