cemadotin and Hypertension

LU 103793 is a synthetic analogue of Dolastatin 15 that inhibits tubulin polymerisation. The aim of this study was to evaluate the efficacy and tolerability of LU 103793 in patients with metastatic breast cancer who had been previously treated with two lines of chemotherapy for advanced disease. Patients received LU 103793 at a dose of 2.5 mg/m(2)/day over 5 min for 5 consecutive days every 3 weeks. Thirty-four patients were enrolled and 23 patients were eligible for the evaluation of efficacy. Eleven patients experienced grade 4 neutropenia. Other related grade 3/4 adverse events included asthenia (three patients), stomatitis (1), myalgia (1) and increase of serum bilirubin (2). The main toxicity was hypertension occurring in seven out of 34 patients. There were no objective responses, 7 patients had stable disease. These results do not support the further evaluation of LU 103793 in metastatic breast cancer patients using this dose and schedule.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Female; Humans; Hypertension; Middle Aged; Neoplasm Metastasis; Oligopeptides

To determine the maximum tolerable dose (MTD), principal toxicity, and pharmacologic behaviour of Cemadotin-HCl, a novel antimitotic peptide.. Cemadotin-HCl (10.0 to 27.5 mg/m2/day every three weeks) was administered as a 24-hour intravenous (i.v.) continuous infusion to patients with advanced cancer. Pharmacokinetic analyses were performed during the first treatment cycle. Blood samples were taken over 48 hours and analyzed by radioimmunoassay.. Hypertension was the dose-limiting toxicity (DLT). This type of toxicity was observed at all dose levels, but grade 3 (CTC) was observed only at dose levels 20.0, 25.0 and 27.5 mg/m2. This effect was reversible but in three patients associated with signs of cardiac ischemia. Other significant toxic effects were neutropenia, asthenia, tumor pain and transient liver enzyme elevation. A linear pharmacokinetics was observed. The best curve fit was obtained with a two-compartment model with a terminal half-life of approximately 10 hours at each dose level, a volume of distribution at steady state of approximately 9 l/m2 and a total clearance of approximately 0.6 l/hour/m2. Neither partial nor complete responses were observed although minor tumor regressions were seen in a patient with carcinoma of unknown primary (CUP) and in another patient with liver metastases from a colon cancer.. Hypertension was the dose-limiting toxicity of Cemadotin-HCl administered as a continuous 24-hour infusion. The recommended dose for further evaluation of its anticancer efficacy in disease-oriented phase II studies with this schedule is 15.0 mg/m2. The nature of the principal cardiovascular toxicity remains unclear. The observed toxicities appeared to be significant but manageable.

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Gastrointestinal Diseases; Growth Inhibitors; Humans; Hypertension; Infusions, Intravenous; Male; Middle Aged; Mitosis; Myocardial Ischemia; Neoplasms; Neutropenia; Oligopeptides; Pain; Survival Analysis; Treatment Outcome

Topics: Antineoplastic Agents; Clinical Trials, Phase II as Topic; Depsipeptides; Heart; Humans; Hypertension; Neutropenia; Oligopeptides; Structure-Activity Relationship