title: 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.
abstract: OBJECTIVE
  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.
authors.affiliation: Vanderbilt-Ingram Cancer Center, 777 Preston Research Building, Nashville, TN 37232-6307, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobayashi
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Lockridge
authors.forename: Mace L
authors.initials: ML
authors.lastname: Rothenberg
authors.forename: Alan B
authors.initials: AB
authors.lastname: Sandler
authors.forename: Cindy L
authors.initials: CL
authors.lastname: O'Bryant
authors.forename: Wendy
authors.initials: W
authors.lastname: Cooper
authors.forename: Scott N
authors.initials: SN
authors.lastname: Holden
authors.forename: Roger D
authors.initials: RD
authors.lastname: Aitchison
authors.forename: Nassim
authors.initials: N
authors.lastname: Usman
authors.forename: Maurice
authors.initials: M
authors.lastname: Wolin
authors.forename: Michele L
authors.initials: ML
authors.lastname: Basche
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D016190:Carboplatin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016337:RNA, Catalytic / Q000009:adverse effects / Q000493:pharmacokinetics*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; C121301:Angiozyme; D016337:RNA, Catalytic; D016190:Carboplatin; D040262:Receptors, Vascular Endothelial Growth Factor; D017239:Paclitaxel