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.
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.
Kobayashi
Hiroyuki
H
Vanderbilt-Ingram Cancer Center, 777 Preston Research Building, Nashville, TN 37232-6307, USA.
Eckhardt
S Gail
SG
Lockridge
Jennifer A
JA
Rothenberg
Mace L
ML
Sandler
Alan B
AB
O'Bryant
Cindy L
CL
Cooper
Wendy
W
Holden
Scott N
SN
Aitchison
Roger D
RD
Usman
Nassim
N
Wolin
Maurice
M
Basche
Michele L
ML
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
D020533:Angiogenesis Inhibitors; C121301:Angiozyme; D016337:RNA, Catalytic; D016190:Carboplatin; D040262:Receptors, Vascular Endothelial Growth Factor; D017239:Paclitaxel