gimatecan in treating patients with recurrent or progressive primary malignant glioma

Conditions: Brain and Central Nervous System Tumors

Summary: rationale: drugs used in chemotherapy, such as gimatecan, work in different ways to stop tumor cells from dividing so they stop growing or die. purpose: this phase i/ii trial is studying the side effects and best dose of gimatecan in treating patients with recurrent or progressive primary malignant glioma.

objectives: primary * determine the maximum tolerated dose (mtd) of gimatecan in patients with recurrent or progressive primary malignant glioma treated with or without concurrent enzyme-inducing anticonvulsant drugs. * determine whether this drug has sufficient activity to warrant further development in these patients. (phase ii) secondary * determine the qualitative and quantitative toxic effects of this drug in these patients. * determine the pharmacokinetic behaviors of this drug in these patients. * correlate the principal toxic effects with the pertinent pharmacokinetic parameters of this drug in these patients. * determine the antitumor activity of this drug in these patients. outline: this is an open-label, dose-escalation, multicenter study. patients are stratified according to the concurrent use of enzyme-inducing anticonvulsant drugs (yes vs no). * phase i: patients receive oral gimatecan once daily on days 1-5. courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. cohorts of 3-6 patients receive escalating doses of gimatecan 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: patients receive gimatecan as in phase i at the mtd. patients are followed for at least 1 month and then every 2 months thereafter. projected accrual: approximately 30-83 patients (30-42 for phase i \[15-21 per stratum\] and 21-41 for phase ii) will be accrued for this study within 24 months.

Eligibility criteria:
disease characteristics: * histologically confirmed malignant glioma (glioblastoma multiforme, anaplastic astrocytoma, or anaplastic oligodendroglioma) * recurrent or progressive primary cns neoplasm by contrast-enhanced mri * tumor progression after prior surgery, radiotherapy, or chemotherapy * measurable or evaluable disease * failed prior standard curative or palliative therapy (phase i only) patient characteristics: age * 18 and over performance status * karnofsky 60-100% life expectancy * at least 3 months hematopoietic * absolute neutrophil count ≥ 2,000/mm\^3 * platelet count ≥ 100,000/mm\^3 hepatic * sgpt and sgot ≤ 1.5 times upper limit of normal (uln) (3 times uln if liver metastases are present) * alkaline phosphatase ≤ 2.5 times uln (5 times uln if liver metastases are present) * bilirubin normal renal * creatinine ≤ 1.5 times uln cardiovascular * no myocardial infarction with the past year * no heart failure (including cardiac insufficiency controlled by digitalis and diuretics) * no irreversible arrhythmias requiring permanent medication * no uncontrolled hypertension gastrointestinal * no gastrointestinal dysfunction that would alter absorption or motility, such as any of the following: * active peptic ulcer * inflammatory bowel disease * known intolerance to lactose * malabsorption syndromes * intestinal sub-occlusion other * not pregnant or nursing * negative pregnancy test * fertile patients must use effective barrier contraception * no active infection * no mentally incapacitated patients * no other concurrent severe disease that would preclude study participation prior concurrent therapy: biologic therapy * no concurrent immunotherapy chemotherapy * see disease characteristics * at least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas) * no more than 1 prior chemotherapy regimen * no other concurrent chemotherapy endocrine therapy * concurrent corticosteroids allowed if dose stable for the past 2 weeks * no concurrent hormonal therapy radiotherapy * see disease characteristics * at least 4 weeks since prior radiotherapy * no concurrent radiotherapy surgery * see disease characteristics * at least 3 weeks since prior surgical resection * no prior gastrointestinal surgery that would affect drug absorption other * more than 4 weeks since prior participation in any other investigational drug study * more than 72 hours since prior systemic antibiotics * no concurrent h2 antagonists, antacids, or proton pump inhibitors * if any of these therapies are necessary, ≥ 3 hours must elapse after gimatecan administration * no other concurrent anticancer therapy * no other concurrent investigational drugs * no other concurrent immunosuppressive agents

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