topotecan in treating patients with recurrent, progressive, or refractory cancer that is metastatic to the lining around the brain

Conditions: Brain and Central Nervous System Tumors

Summary: rationale: drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. purpose: phase i trial to study the effectiveness of intrathecal or intraventricular topotecan in treating recurrent, progressive, or refractory cancer that is metastatic to the lining around the brain.

objectives: * determine the maximum tolerated dose of intrathecal or intraventricular topotecan in patients with recurrent, progressive, or refractory leptomeningeal disease. * determine the toxicity of this regimen in these patients. * determine the pharmacokinetics of this regimen in these patients. * determine the anti-tumor activity of this regimen in these patients. outline: this is a dose-escalation study. patients are stratified according to disease (leukemia or lymphoma vs solid tumor or other malignancy). patients receive topotecan intrathecally or intraventricularly continuously on days 1-7. treatment repeats every 21 days for up to 7 courses in the absence of disease progression or unacceptable toxicity. cohorts of 3-6 patients receive escalating doses of topotecan until the maximum tolerated dose (mtd) is determined. the mtd is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose- limiting toxicity. patients are followed for 6 months. projected accrual: a maximum of 50 patients (25 per stratum) will be accrued for this study.

Eligibility criteria:
disease characteristics: * histologic or tumor marker confirmation of malignancy at original diagnosis * neoplastic meningitis/leptomeningeal metastasis refractory to conventional therapy and other therapies of higher priority, defined as: * stratum a: * small non-cleaved lymphoma (burkitt's) with any l-3 blast in cerebrospinal fluid (csf) * any other lymphoma or leukemia with csf cell count greater than 5/mm3 and evidence of blast cells by cytology or cytospin preparation or * stratum b: * solid tumor or other malignancy with presence of tumor cells on cytospin or positive cytology or neuroimaging evidence of leptomeningeal tumor by mri or ct myelogram * no leptomeningeal leukemia or lymphoma with concurrent bone marrow relapse * no clinical evidence of untreated obstructive hydrocephalus or compartmentalization of the csf patient characteristics: age: * 65 and under performance status: * lansky 50-100% (age 16 and under) * karnofsky 50-100% or ecog 0-3 (over age 16) life expectancy: * at least 2 months hematopoietic: * stratum b: * absolute neutrophil count at least 750/mm\^3 * platelet count at least 75,000/mm\^3 (transfusion independent) * hemoglobin at least 10.0 g/dl (red blood cell transfusions allowed) hepatic: * bilirubin no greater than 1.5 times normal * sgot or sgpt less than 2.5 times upper limit of normal renal: * creatinine no greater than 1.5 mg/dl or * creatinine clearance or radioisotope glomerular filtration rate at least 70 ml/min neurologic: * seizures allowed if well controlled and on anticonvulsants * cns toxicity no greater than grade 2 other: * not pregnant or nursing * negative pregnancy test * fertile patients must use effective contraception * no uncontrolled infections * hiv allowed prior concurrent therapy: biologic therapy: * no concurrent immunomodulating agents (stratum b) * no stem cell transplantation (stratum a) chemotherapy: * at least 2 weeks since prior chemotherapy (4 weeks for nitrosoureas) * no other concurrent cancer chemotherapy (stratum b) * other concurrent systemic cancer chemotherapy for leukemia or lymphoma allowed with the following restrictions: * no oral or iv topotecan * no moderate or high-dose iv or subcutaneous cytarabine (greater than 1.0 g/m2 per day) * no moderate or high-dose iv methotrexate (greater than 1 g/m2 per day) * no iv thiotepa * no myeloablative chemotherapy * no intrathecal or intraventricular chemotherapy endocrine therapy: * concurrent corticosteroids allowed only for treatment of increased intracranial pressure in patients with cns tumors * no concurrent intrathecal or intraventricular hydrocortisone radiotherapy: * at least 4 weeks since completion of radiotherapy to the brain or spine and recovered * concurrent radiotherapy to localized painful lesions producing acute neurologic dysfunction allowed provided at least 1 measurable lesion is not irradiated * no concurrent craniospinal or whole-brain radiotherapy surgery: * not specified other: * recovered from prior therapy * at least 7 days since prior investigational drug * no other concurrent intrathecal or intraventricular therapy for leptomeningeal disease

Keywords: leptomeningeal metastases