A phase I dose escalation and pharmacokinetic study of vatalanib (PTK787/ZK 222584) in combination with paclitaxel in patients with advanced solid tumors

E. Gabriela Chiorean, Srikar Malireddy, Anne E. Younger, David R. Jones, Mary Jane Waddell, Melissa I. Sloop, Menggang Yu, Stephen D. Hall, Bryan Schneider, Christopher J. Sweeney

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Purpose: 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. Methods:Patients were treated with escalating doses of weekly paclitaxel (75-85 mg/m2), 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. Results: 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 disease ≥4 months, including patients previously treated with paclitaxel. Conclusions: The MTD for weekly paclitaxel plus daily PTK/ZK is 75 mg/m2 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.

Original languageEnglish (US)
Pages (from-to)441-448
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume66
Issue number3
DOIs
StatePublished - Aug 1 2010

    Fingerprint

Keywords

  • Paclitaxel
  • Phase I
  • PTK/ZK
  • VEGFR

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this