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

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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/m2 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.

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Authors and Affiliations

  1. Department of Medicine, Indiana University Simon Cancer Center, Indianapolis, IN, USA

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

  2. Department of Biostatistics, Indiana University, Indianapolis, IN, USA

    Menggang Yu

  3. Department of Medicine, Lank Center for Genitourinary Oncology, Dana Farber Cancer Institute, 44 Binney Street, Rm 1230, Boston, MA, 02115, USA

    Christopher J. Sweeney

Authors
  1. E. Gabriela Chiorean
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  2. Srikar Malireddy
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  3. Anne E. Younger
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  4. David R. Jones
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  5. Mary-Jane Waddell
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  6. Melissa I. Sloop
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  7. Menggang Yu
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  8. Stephen D. Hall
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  9. Bryan Schneider
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  10. Christopher J. Sweeney
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Corresponding author

Correspondence to Christopher J. Sweeney.

Additional information

Supported by Novartis Pharmaceuticals; General Clinical Research Center at Indiana University School of Medicine M01RR00750.

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Chiorean, E.G., Malireddy, S., Younger, A.E. et al. A phase I dose escalation and pharmacokinetic study of vatalanib (PTK787/ZK 222584) in combination with paclitaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol 66, 441–448 (2010). https://doi.org/10.1007/s00280-009-1179-2

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  • DOI: https://doi.org/10.1007/s00280-009-1179-2

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