brostallicin in treating patients with recurrent or refractory multiple myeloma

Conditions: Multiple Myeloma and Plasma Cell Neoplasm

Summary: rationale: drugs used in chemotherapy such as brostallicin use different ways to stop cancer cells from dividing so they stop growing or die. purpose: phase i/ii trial to study the effectiveness of brostallicin in treating patients who have recurrent or refractory multiple myeloma.

objectives: * determine the objective tumor response rate (confirmed complete response and confirmed partial response) of brostallicin in patients with recurrent or refractory multiple myeloma. * determine the maximum tolerated dose of this drug in these patients. * determine the time to and duration of response, time to treatment failure, time to tumor progression, and survival in patients treated with this drug. * determine the safety and tolerability of this drug in these patients. * determine the pharmacokinetics of this drug in these patients. * correlate baseline whole blood levels and activity of glutathione with clinical outcome in patients treated with this drug. outline: this is an open-label, multicenter, dose-escalation study. * phase i: patients receive brostallicin iv over 10-30 minutes on day 1. courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. cohorts of 3-6 patients receive escalating doses of brostallicin until the maximum tolerated dose (mtd) is determined. the mtd is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity. * phase ii: additional patients are accrued and treated at the mtd of brostallicin as in phase i. patients are followed every 2 months. projected accrual: a total of 23-52 patients will be accrued for this study.

Eligibility criteria:
disease characteristics: * confirmed diagnosis of multiple myeloma based on prior or current demonstration of the following criteria\*: * major criteria: * plasmacytoma on tissue biopsy * bone marrow plasmacytosis with at least 30% plasma cells * monoclonal globulin spike on serum electrophoresis exceeding 3.5 g/dl for igg peaks or 2.0 g/dl for iga peaks; greater than 1,000 mg/24hr of kappa or gamma light chain excretion on urine electrophoresis in the absence of amyloidosis * minor criteria: * bone marrow plasmacytosis with 10% to 30% plasma cells * monoclonal globulin spike present but less than levels in major criterion iii above * lytic bone lesions * residual normal immunoglobulin m (igm) no greater than 0.5 g/dl, iga no greater than 0.1 g/dl, or igg no greater than 0.6 g/dl note: \*diagnosis of multiple myeloma requires a minimum of 1 major and 1 minor criterion (i and a together is not sufficient; must be i and b, i and c, i and d; ii and b, ii and c, ii and d; iii and a, iii and c, iii and d) or 3 minor criteria that must include a and b (a, b, and c; a, b, and d) * measurable disease defined by 1 of the following values: * serum myeloma (m) protein (igg or iga) level greater than 1.0 g/dl * urine m protein (light chain disease) at least 300 mg/24hr * soft tissue plasmacytoma with bidimensional measurement at least 20 x 20 mm (10 x 10 mm if spiral ct scan is used) * must have progressed during or within 12 months of discontinuing prior myelosuppressive chemotherapy (e.g., vincristine, doxorubicin, and dexamethasone (vad) or melphalan) or not responded after 2 courses of prior myelosuppressive chemotherapy * no indolent or smoldering myeloma or localized plasmacytoma * no known brain or leptomeningeal disease unless such lesions were previously irradiated, are currently not being treated with corticosteroids, and are associated with no clinical symptoms patient characteristics: age * 18 and over performance status * eastern cooperative oncology group (ecog) 0-2 life expectancy * at least 12 weeks hematopoietic * absolute neutrophil count at least 1,500/mm\^3 (at least 1,000/mm\^3 if neutropenia due to replacement of the normal bone marrow cells by myeloma cells) * platelet count at least 100,000/mm\^3 (at least 50,000/mm\^3 if thrombocytopenia due to replacement of the normal bone marrow cells by myeloma cells) * hemoglobin at least 8.0 g/dl (no transfusion allowed) * no hyperviscosity syndrome hepatic * bilirubin no greater than 1.5 times upper limit of normal (uln) * serum glutamate oxaloacetate transaminase (sgot) no greater than 2.5 times uln * alkaline phosphatase no greater than 2.5 times uln renal * creatinine no greater than 3.0 times uln * calcium no greater than 12 mg/dl other * not pregnant or nursing * negative pregnancy test * fertile patients must use effective contraception * willing and able to comply with scheduled visits, treatment plan, laboratory tests, and sampling for study analysis * hiv negative * no other malignancy within the past 5 years except adequately treated nonmelanoma skin cancer or carcinoma in situ of the cervix * no aids-related illness * no active infectious process or other severe concurrent disease that would make the patient inappropriate for study entry * no mental incapacity or psychiatric illness that would preclude giving informed consent or completing follow-up prior concurrent therapy: biologic therapy * see chemotherapy * no concurrent anticancer biological response modifiers * no concurrent immunotherapy * no concurrent sargramostim (gm-csf) chemotherapy * see disease characteristics * more than 2 years since prior high-dose chemotherapy with autologous bone marrow transplantation or stem cell support * more than 4 weeks since prior myelosuppressive chemotherapy * no other concurrent anticancer chemotherapy endocrine therapy * see disease characteristics * no concurrent anticancer hormonal therapy * no concurrent chronic steroids * acute pulse dosing required for treatment of a concurrent medical condition is allowed, provided treatment duration is no greater than 2 weeks * no concurrent corticosteroids (e.g., dexamethasone) radiotherapy * more than 14 days since prior radiotherapy * no prior radiotherapy to more than 25% of bone marrow * no plans for radiotherapy within the next 6 months * concurrent palliative radiotherapy for skeletal pain allowed surgery * more than 14 days since prior surgery * no plans for surgery within the next 6 months other * acute toxic effects of prior therapy (except for alopecia and neurotoxicity) must have resolved to grade 0, 1, or the patient's baseline * treatment-related neurotoxicity must have resolved to the patient's baseline, not to exceed grade 2 * chronic bisphosphonates for bone pain allowed only for maintenance doses * more than 2 weeks since prior nonmyelosuppressive antimyeloma therapy * more than 2 weeks since prior macrolide antibiotics * no other concurrent investigational agents * no concurrent macrolide antibiotics * no concurrent participation in another treatment clinical study

Keywords: stage iii multiple myeloma refractory multiple myeloma