A phase I dose escalation and pharmacokinetic study of vatalanib (PTK787/ZK 222584) in combination with paclitaxel in patients with advanced solid tumors
| Autor: | M. J. Waddell, E. Gabriela Chiorean, Bryan P. Schneider, Srikar R. Malireddy, Christopher Sweeney, Stephen D. Hall, David R. Jones, Melissa I. Sloop, Anne Younger, Menggang Yu |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Male Cancer Research Vatalanib animal structures Maximum Tolerated Dose Paclitaxel Pyridines medicine.drug_class Pharmacology Toxicology Tyrosine-kinase inhibitor chemistry.chemical_compound Pharmacokinetics Neoplasms Antineoplastic Combined Chemotherapy Protocols Dose escalation medicine Humans Drug Interactions Pharmacology (medical) In patient Transaminases Aged Dose-Response Relationship Drug business.industry Advanced stage Weekly paclitaxel Middle Aged Treatment Outcome Oncology chemistry Phthalazines Female business |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 66:441-448 |
| ISSN: | 1432-0843 0344-5704 |
| Popis: | To define the maximum-tolerated dose (MTD) for weekly paclitaxel administered in combination with daily vatalanib (PTK787/ZK 222584, PTK/ZK) and assess for a drug-drug interaction.Patients were treated with escalating doses of weekly paclitaxel (75-85 mg/m(2)), and daily PTK/ZK (250-1,000 mg). During the first cycle only, paclitaxel was given on days 1 and 15, and PTK/ZK on days 3-28. Pharmacokinetic studies were conducted on cycle 1 days 1 and 15 for paclitaxel, and on cycle 1 day 15 for PTK/ZK. Therapy was given until disease progression.Twenty-seven patients were accrued to four dose levels. Two of five patients treated with paclitaxel 85 mg/m(2) and PTK/ZK 1,000 mg had Grade 3 transaminase elevation as dose-limiting toxicity. Paired PK analyses demonstrated a significant increase in paclitaxel clearance on day 15 (p = 0.006). Activity included one partial response and 11 patients with stable diseaseor =4 months, including patients previously treated with paclitaxel.The MTD for weekly paclitaxel plus daily PTK/ZK is 75 mg/m(2) and 750 mg. PK analysis revealed a significant drug-drug interaction, with an increase in paclitaxel clearance. This combination was well tolerated with evidence of anti-cancer activity and provides guidance for phase 2 planning. |
| Databáze: | OpenAIRE |
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