A phase I pharmacological and biological study of PI-88 and docetaxel in patients with advanced malignancies
| Autor: | Scott N. Holden, Laura Q M Chow, Kat Davis, S. Grolnic, Michele Basche, Kaye L. Roberts, Mark Morrow, Brian R. Creese, Lia Gore, Daniel L. Gustafson, R. S. Addison, Cindy L. O'Bryant, S. Gail Eckhardt |
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| Rok vydání: | 2008 |
| Předmět: |
Adult
Male Vascular Endothelial Growth Factor A Cancer Research Gastrointestinal Diseases Angiogenesis Oligosaccharides Angiogenesis Inhibitors Docetaxel Pharmacology Platelet Factor 4 Toxicology Drug Administration Schedule Article Endoglycosidase Neoplasms Antineoplastic Combined Chemotherapy Protocols medicine Humans Pharmacology (medical) Heparanase Fatigue Aged Glucuronidase biology Heparin business.industry Biological activity Middle Aged Combined Modality Therapy Neoplasm Proteins Clinical trial Oncology Enzyme inhibitor Toxicity Cancer research biology.protein Female Fibroblast Growth Factor 2 Partial Thromboplastin Time Taxoids Maximum Allowable Concentration business medicine.drug |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 63:65-74 |
| ISSN: | 1432-0843 0344-5704 |
| DOI: | 10.1007/s00280-008-0712-z |
| Popis: | This study evaluated the safety, toxicity, pharmacological properties and biological activity of PI-88, a heparanase endoglycosidase enzyme inhibitor, with fixed weekly docetaxel in patients with advanced solid malignancies.This was a phase I study to determine the maximal-tolerated dose of escalating doses of PI-88 administered subcutaneously for 4 days per week, along with docetaxel 30 mg/m(2) given on days 1, 8, 15 of a 28-day schedule.Sixteen patients received a total of 42 courses of therapy. No dose-limiting toxicities were observed despite escalation to the highest planned dose level of PI-88 (250 mg/day). Frequent minor toxicities included fatigue (38%), dysgeusia (28.5%), thrombocytopenia (12%), diarrhea (14%), nausea (12%), and emesis (10%) in the 42 courses. No significant bleeding complications were observed. One patient developed a positive anti-heparin antibody test/serotonin releasing assay with positive anti-platelet factor 4/PI-88 antibodies and grade 1 thrombocytopenia in cycle 5, and was withdrawn from the study without any sequelae. PI-88 plasma concentrations (mirrored by APTT) and urinary elimination were linear and dose-proportional. Docetaxel did not alter the pharmacokinetic (PK) profile of PI-88, nor did PI-88 affect docetaxel PK. No significant relationship was determined between plasma or urine FGF-2, or plasma VEGF levels and PI-88 dose/response. Although no objective responses were observed; 9 of the 15 evaluable patients had stable disease for greater than two cycles of therapy.PI-88 administered at 250 mg/day for 4 days each week for 3 weeks with docetaxel 30 mg/m(2) on days 1, 8 and 15, every 28 days, was determined to be the recommended dose level for phase II evaluation. This combination was well tolerated without severe toxicities or PK interactions. |
| Databáze: | OpenAIRE |
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