Cancer Chemotherapy and Pharmacology

, Volume 56, Issue 4, pp 329–336 | Cite as

Safety and pharmacokinetic study of RPI.4610 (ANGIOZYME), an anti-VEGFR-1 ribozyme, in combination with carboplatin and paclitaxel in patients with advanced solid tumors

  • Hiroyuki Kobayashi
  • S. Gail Eckhardt
  • Jennifer A. Lockridge
  • Mace L. Rothenberg
  • Alan B. Sandler
  • Cindy L. O’Bryant
  • Wendy Cooper
  • Scott N. Holden
  • Roger D. Aitchison
  • Nassim Usman
  • Maurice Wolin
  • Michele L. Basche
Original Article

Abstract

Purpose

RPI.4610 (ANGIOZYME) is a chemically stabilized ribozyme targeting vascular endothelial growth factor receptor 1. The purpose of this study was to evaluate the safety and pharmacokinetics of RPI.4610 in combination with carboplatin and paclitaxel in patients with advanced solid tumors.

Methods

The study used a sequential treatment design evaluating a single dose level for all three drugs: paclitaxel 175 mg m−2 and carboplatin AUC=6 on day 1 of a 21-day cycle, and RPI.4610 100 mg m−2 day−1 beginning on day 8 and continuing daily thereafter. Pharmacokinetic samples were drawn on day 1 of courses 1 (chemotherapy alone) and 2 (chemotherapy+RPI.4610), and on day 8 of course 1 (RPI.4610 alone). Ratios were generated by comparing the pharmacokinetic parameters for the combination of carboplatin with paclitaxel when administered alone or together with RPI.4610.

Results

Twelve patients were enrolled in this trial and received two to six courses of treatment each. The most common grade 3–4 toxicities were neutropenia (three patients), thrombocytopenia (three patients), pain (three patients), anemia (two patients) and fatigue (two patients). The ratio of the mean maximum plasma concentration (Cmax) for carboplatin when administered with paclitaxel alone versus when administered with paclitaxel and RPI.4610 was 1.07 (90% confidence interval, 0.77–1.37). Similarly, the ratio of the mean AUC0-last for carboplatin was 1.04 (0.73–1.35). For paclitaxel the ratio of the mean Cmax when administered with carboplatin alone versus with carboplatin and RPI.4610 was 1.17 (1.03–1.31), and the ratio of the mean AUC0–last was 1.17 (1.04–1.30). Objective tumor responses were observed and included one patient with a complete response (bladder cancer) and one patient with a partial response (esophageal cancer).

Conclusions

These results indicate that RPI.4610, carboplatin, and paclitaxel can be administered safely in combination without substantial pharmacokinetic interactions.

Keywords

ANGIOZYME Carboplatin Paclitaxel Pharmacokinetics Ribozyme Vascular endothelial growth factor receptor Angiogenesis inhibitors 

Notes

Acknowledgements

This trial was supported by Sirna Therapeutics, Chiron, and NIH Grant RR00095. We thank Drs Jordan D. Berlin and Bruce J. Roth (Vanderbilt-Ingram Cancer Center), Dr Andrew S. Pierson and Martha S. Persky, R.N. (University of Colorado Cancer Center) for managing all clinical aspects of some study patients. We are also grateful to Drs Gary S. Gordon and Vann P. Parker for their help in performing pharmacokinetic analyses.

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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Hiroyuki Kobayashi
    • 1
  • S. Gail Eckhardt
    • 2
  • Jennifer A. Lockridge
    • 3
  • Mace L. Rothenberg
    • 1
  • Alan B. Sandler
    • 1
  • Cindy L. O’Bryant
    • 2
  • Wendy Cooper
    • 1
  • Scott N. Holden
    • 2
  • Roger D. Aitchison
    • 3
  • Nassim Usman
    • 3
  • Maurice Wolin
    • 4
  • Michele L. Basche
    • 2
  1. 1.Vanderbilt-Ingram Cancer CenterNashvilleUSA
  2. 2.Anschutz Cancer PavilionUniversity of Colorado Cancer CenterAuroraUSA
  3. 3.Sirna TherapeuticsBoulderUSA
  4. 4.Chiron CorporationEmeryvilleUSA

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