Nassim Usman

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

PurposeRPI.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.MethodsThe study used a sequential treatment design evaluating a single dose level for all three drugs: paclitaxel 175xa0mgxa0m−2 and carboplatin AUC=6 on day 1 of a 21-day cycle, and RPI.4610 100xa0mgxa0m−2xa0day−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.ResultsTwelve 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).ConclusionsThese results indicate that RPI.4610, carboplatin, and paclitaxel can be administered safely in combination without substantial pharmacokinetic interactions.

Crystallization and preliminary X‐ray diffraction analysis of double‐helical RNA octamers

Single crystals of a chemically synthesized self-complementary RNA octamer with sequence r(CCCCGGGG) have been obtained by screening 50 different conditions at room temperature using a standard sparse-matrix sampling method. Two crystal forms with different morphologies grew under diverse crystallization conditions within days by hanging-drop vapor diffusion. Hexagonal crystals with space group P6(1)22 (one strand per asymmetric unit) and unit-cell dimensions a = b = 39.73 and c = 58.55 A, diffracted to 2.6 A. Rhombohedral crystals with space group R32 (one duplex per asymmetric unit) and unit-cell dimensions a = b = 42.38 and c = 131.70 A, (hexagonal setting) diffracted beyond 1.5 A. Data sets for both crystal forms were collected on image-plate/rotating-anode generator equipment and structure determinations and refinements are under way.