Phase I, pharmacokinetic, and biological studies of TSU-68, a novel multiple receptor tyrosine kinase inhibitor, administered after meals with solid tumors
| Autor: | Tomohide Tamura, Noboru Yamamoto, Hitoshi Arioka, Tatsu Shimoyama, Yutaka Ueda, Yasuhide Yamada, Haruyasu Murakami |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Adult
Male Vascular Endothelial Growth Factor A medicine.medical_specialty Cancer Research Indoles medicine.drug_class Angiogenesis Pharmacokinetic Administration Oral Angiogenesis Inhibitors Pharmacology Biology Receptor tyrosine kinase inhibitor Toxicology Tyrosine-kinase inhibitor Drug Administration Schedule chemistry.chemical_compound Phase I Growth factor receptor Internal medicine Neoplasms Solid tumors Plasminogen Activator Inhibitor 1 medicine Biomarkers Tumor Humans Pharmacology (medical) Pyrroles Aged Dose-Response Relationship Drug Middle Aged Protein-Tyrosine Kinases medicine.disease Postprandial Period Oxindoles Vascular endothelial growth factor Endocrinology chemistry Tolerability Oncology Toxicity Original Article Female Propionates Tyrosine kinase Progressive disease |
| Zdroj: | Cancer Chemotherapy and Pharmacology |
| ISSN: | 1432-0843 0344-5704 |
| Popis: | Purpose TSU-68 is a low molecular weight inhibitor of the tyrosine kinases for vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor β, and fibroblast growth factors receptor 1. In this study, we assessed the recommended dose with TSU-68 administration of twice-daily (b.i.d.) or thrice-daily (t.i.d.) after meals for 4 weeks in Japanese patients with solid tumors based on the safety and tolerability and investigated the relationship between angiogenesis biomarker and clinical outcomes. Methods The study design was a dose-escalation method with alternating enrollment of b.i.d. administration and t.i.d. administration after meal by traditional three-patient cohort. Results We enrolled 24 patients at doses of 200, 400, and 500 mg/m2 b.i.d. or 200 and 400 mg/m2 t.i.d. No dose-limiting toxicity (DLT) occurred in the 200 mg/m2 b.i.d. or t.i.d., and 3 patients experienced DLTs at 400 mg/m2 b.i.d. or 400 mg/m2 t.i.d. As main toxicity, blood albumin decreased, malaise, diarrhea, alkaline phosphatase increased, anorexia, abdominal pain, nausea, and vomiting were observed as almost all grade 1–2. There were no apparent differences in pharmacokinetic parameters between days 2 and 28 after the repeated b.i.d. and t.i.d. doses. Although tumor shrinkage was not observed, the disease control rate was 41.7%. As an angiogenesis-related factor of stratified analysis, plasma vascular endothelial growth factor and plasminogen activator inhibitor-1 were detected as a significant increase with progressive disease patients. Conclusions A recommended dosage of TSU-68 for this administration schedules was estimated to be 400 mg/m2 or less b.i.d. |
| Databáze: | OpenAIRE |
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