Abstract C232: ALB‐109564, a novel tubulin inhibitor with improved efficacy over vinorelbine, is better tolerated when dosed iv versus ip, leading to improved activity in human tumor xenograft studies

Purpose: ALB‐109564 is a novel semi‐synthetic Vinca alkaloid which is currently in a Phase I clinical trial. The antitumor activity of ALB‐109564 was compared to vinorelbine in human tumor xenograft studies when dosed ip and iv. Methods: The maximum tolerated dose (MTD) of ALB‐109564 and vinorelbine was determined in athymic nude mice using both ip and iv dosing on q4dx4 and q7dx4 schedules. Athymic nude mice (n = 10) were implanted sc with a number of human tumor cell lines. Following establishment of measurable tumors, mice received equivalent therapeutic doses, based on their MTDs, of vinorelbine and ALB‐109564. Vinorelbine and ALB‐109564 were compared by dosing ip (q4dx4) in a panel of five xenografts (H460 NSCLC, Colo205 colon cancer, PC3 prostate cancer, H69 SCLC, and MX‐1 breast cancer). Additionally, a comparison of ALB‐109564 and vinorelbine was run dosing iv on a q7dx4 schedule in two xenograft models (PC3 and H460). Results: It was discovered that ALB‐109564 and vinorelbine were better tolerated when dosed iv rather than ip, allowing higher dose levels of both agents. For example, the MTD for ALB‐109564 using the q4dx4 schedule was 6 mpk ip compared with 14 mpk iv. ALB‐109564 demonstrated antitumor activity superior to vinorelbine when dosed at their respective MTDs ip. Statistically significant tumor growth delays (TGDs) were observed with ALB‐109564 in four of the five xenografts studied while vinorelbine did not significantly delay tumor growth in any of the models when dosing ip. A comparison of the two agents dosed iv in the PC3 and H460 xenograft models showed that both agents induced significant TGDs in both models with ALB‐109564 showing superior efficacy in the H460 study (35.7 days TGD vs. 15.7 days at respective MTDs). Conclusions: Preclinical evaluation of tubulin inhibitor ALB‐109564 (12′‐methylthiovinblastine dihydrochloride) demonstrated in vivo oncolytic activity against several human tumor cell types in xenograft models greater than that seen with vinorelbine. These results demonstrate that minor structural modifications of vinca alkaloids can have a large impact on activity. Based on these results a Phase I clinical study with ALB‐109564 was initiated in August 2008 and is ongoing through dose‐escalation. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C232.