elsamicin-a and Neoplasms

To test the antitumor activity of Elsamitrucin in metastatic cancer of the breast, colon and rectum, non-small cell lung and ovary.. Eligibility required histologically proven cancer. Patients with colorectal or non-small cell lung cancer could not have received prior chemotherapy. Patients were entered if WHO PS was < or = 2 and organ functions were normal. Treatment consisted of Elsamitrucin 25 mg/m2/week given as a 5-10 min infusion for at least 3-6 weekly doses.. One hundred and five patients entered the studies, 97 were eligible, 94 are evaluable for toxicity and 75 for response. Toxicity mainly consisted of mild nausea/vomiting, and less frequently reversible hepatotoxicity and malaise. No objective responses were seen.. Elsamitrucin at this dose and schedule is not an active drug in metastatic breast cancer, colorectal cancer, non-small cell lung cancer or ovarian cancer.

Topics: Adolescent; Adult; Aged; Aminoglycosides; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Ovarian Neoplasms

Elsamitrucin (BMY-28090) is an antitumor antibiotic first described in 1985 that has significant oncolytic activity against a number of murine tumors including P388, L1210, B16 and M5076, as well as against MX1 and HCT116 xenografts. Preclinical toxicology studies of elsamitrucin revealed edema of multiple organs associated with hypoproteinemia and, at lethal doses, severe multiorgan toxicity. We conducted a phase I clinical trial (31 patients) of elsamitrucin administered as a 10-min i.v. infusion every 3 weeks. The starting dose (0.6 mg/m2) was 1/3 of the dog low toxic dose. The maximum tolerated dose was 30 mg/m2. Dose-limiting toxicity was reversible hepatic dysfunction manifested by elevated transaminase levels not associated with bilirubin, alkaline phosphatase, or lactate dehydrogenase elevations. Other toxicities included nausea, vomiting, malaise, and phlebitis. Because the hepatic toxicity was brief and reversible, a subsequent study (18 patients) was conducted with elsamitrucin administered every 2 weeks. Reversible grade 3 hepatotoxicity was again observed at 30 mg/m2. Plasma and urine samples from patients receiving doses of 0.6-36 mg/m2 were analyzed for drug content. The maximum plasma concentration and area under the plasma concentration versus time curve values increased linearly with doses up to 25 mg/m2 but not at higher doses. The terminal half-lives, total body clearances, and volume of distribution were 36-60 h, 10-19 liters/h/m2, and 400-1100 liters/m2, respectively. Less than 5% was excreted in the urine in 24 h as parent compound. Bile was collected from one patient with an indwelling biliary catheter. Approximately 22% of the dose was excreted in 48 h, suggesting that biliary excretion of elsamitrucin may be an important route of drug elimination. Based on reversible hepatic toxicity, the phase II recommended dose of elsamitrucin is 25 mg/m2 every 2 weeks.

Topics: Adult; Aged; Aminoglycosides; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Drug Administration Schedule; Drug Evaluation; Female; Humans; Infusions, Intravenous; Liver; Male; Middle Aged; Neoplasms