A phase I pharmacokinetic study of PM00104 (Zalypsis®) administered as a 24-h intravenous infusion every 3 weeks in patients with advanced solid tumors
| Autor: | E. Sicart, M. J. Carreras, Jaume Capdevila, Caroline O. Michie, Martin Cullell-Young, Sally Clive, C. Coronado, A. Soto Matos-Pita, Carmen Kahatt, A. Piera, C. Fernandez Teruel, Esther Casado, Josep Tabernero, Mariano Siguero |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
Male Cancer Research Treatment outcome Antineoplastic Agents Tumor cells Pharmacology Toxicology Severity of Illness Index chemistry.chemical_compound Pharmacokinetics Neoplasms Tetrahydroisoquinolines Humans Medicine Pharmacology (medical) In patient Infusions Intravenous Aged Antitumor activity Dose-Response Relationship Drug business.industry Tetrahydroisoquinoline Alkaloid Middle Aged Phase i study Treatment Outcome Oncology chemistry Area Under Curve Female business |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 71:1247-1254 |
| ISSN: | 1432-0843 0344-5704 |
| DOI: | 10.1007/s00280-013-2119-8 |
| Popis: | PM00104 (Zalypsis) is a synthetic tetrahydroisoquinoline alkaloid with potent antiproliferative activity against tumor cell lines. This phase I study evaluated the safety, dose-limiting toxicities (DLTs), recommended dose for phase II trials (RD), pharmacokinetics (PK) and preliminary antitumor activity of PM00104 as a 24-h intravenous (i.v.) infusion every 3 weeks (q3wk).Thirty-seven patients with refractory advanced solid tumors received PM00104 in a toxicity-guided dose escalation study design (3 + 3 patients per cohort). Plasma samples were collected for PK analysis.DLTs comprised severe neutropenia lasting5 days (n = 4 patients), vomiting, thrombocytopenia, transaminase increases (n = 2 each), fatigue, tumor pain, myalgia, muscle stiffness, creatine phosphokinase increase and dosing delay2 weeks due to moderate fatigue (n = 1 each). The RD was 4.0 mg/m(2). Most PM00104-related adverse events at the RD were mild or moderate; the most common were nausea, vomiting and fatigue. Myelosuppression and transaminase increases were transient and manageable. PK parameters increased linearly with dose. Higher PM00104 PK exposure was related to a decrease in hemoglobin, neutrophils, platelets and white blood cells. Area under the curve was directly correlated with both incidence and severity of nausea and vomiting. Three patients with hepatocellular carcinoma, esophageal adenocarcinoma and prostate adenocarcinoma had response evaluation criteria in solid tumors stable disease ≥3 months.PM00104 given as 24-h i.v. infusion q3wk has predictable and manageable toxicity, but resulted in more myelotoxicity (because of the higher dose level achieved as the RD) and a similar drug clearance compared to 1-h infusion schedules. Preliminary evidence of antitumor activity was observed. |
| Databáze: | OpenAIRE |
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