Annals of oncology : official journal of the European Society for Medical Oncology · 1998
Clinical and pharmacologic phase I study of Cemadotin-HCl (LU103793), a novel antimitotic peptide, given as 24-hour infusion in patients with advanced cancer. A study of the Arbeitsgemeinschaft Internistische Onkologie (AIO) Phase I Group and Arbeitsgruppe Pharmakologie in der Onkologie und Haematologie (APOH) Group of the German Cancer Society.
Клиническое исследованиеКлиническое исследование I фазыСтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Mross K, Berdel W E, Fiebig H H, Velagapudi R, von Broen I M, Unger C
Аннотация
PURPOSE: To determine the maximum tolerable dose (MTD), principal toxicity, and pharmacologic behaviour of Cemadotin-HCl, a novel antimitotic peptide.
PATIENTS AND METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
PATIENTS AND METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
Предметные рубрики MeSH
AdultAgedAntineoplastic AgentsArea Under CurveDose-Response Relationship, DrugDrug Administration ScheduleFemaleGastrointestinal DiseasesGrowth InhibitorsHumansHypertensionInfusions, IntravenousMaleMiddle AgedMitosisMyocardial IschemiaNeoplasmsNeutropeniaOligopeptidesPainSurvival AnalysisTreatment Outcome