Original Article

Cancer Chemotherapy and Pharmacology

, Volume 56, Issue 4, pp 329-336

First online:

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 KobayashiAffiliated withVanderbilt-Ingram Cancer Center
  • , S. Gail EckhardtAffiliated withAnschutz Cancer Pavilion, University of Colorado Cancer Center
  • , Jennifer A. LockridgeAffiliated withSirna Therapeutics
  • , Mace L. RothenbergAffiliated withVanderbilt-Ingram Cancer Center Email author 
  • , Alan B. SandlerAffiliated withVanderbilt-Ingram Cancer Center
  • , Cindy L. O’BryantAffiliated withAnschutz Cancer Pavilion, University of Colorado Cancer Center
  • , Wendy CooperAffiliated withVanderbilt-Ingram Cancer Center
  • , Scott N. HoldenAffiliated withAnschutz Cancer Pavilion, University of Colorado Cancer Center
  • , Roger D. AitchisonAffiliated withSirna Therapeutics
    • , Nassim UsmanAffiliated withSirna Therapeutics
    • , Maurice WolinAffiliated withChiron Corporation
    • , Michele L. BascheAffiliated withAnschutz Cancer Pavilion, University of Colorado Cancer Center

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

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