Abstract 2787: Antitumor activity and toxicity of FL118, a novel IAP/Bcl-2 antiapoptotic genes-selective inhibitor, in animal models of human tumor via the clinic-compatible intravenous (i.v.) routes

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Our previous studies on antitumor activity of FL118, a survivin/Mcl-1/XIAP/cIAP2-selective inhibitor, in mouse models of human colon and head-&-neck xenografts have showed exceptional antitumor activity with tolerated toxicity via intraperitoneal (i.p.) routs with once a week for 4 weeks (weekly x 4) schedule. However, several issues need to be addressed in order to move FL118 into clinical trials. First, the previous formulation (0.05 mg/ml FL118, 5% DMSO, 20% Tween 80 and 75% saline) used in the i.p, route is not suitable for clinical application. Second, due to toxicity of this formulation solution itself, FL118 reaches its maximum tolerated dose (MTD) in frequent drug administration schedules (e.g. daily x 5 or every other day x 5) before showing significant antitumor efficacy. Additionally, the low concentration of FL118 in the formulated solution restricts its escalation to higher dose due to drug solubility issues. Here we report antitumor activity and toxicity (body weight loss) of FL118 formulated in a Tween 80-free formula for the i.v. route administration of drug. Previous studies on FL118 revealed that the MTD with i.p. administration of FL118 formulated in the Tween 80-contraining formula, is 0.2 mg/kg in the daily x 5 schedule (5 does); 0.5 mg/kg in the every other day for three doses (on day 0, 2 & 4, q2 x 3, 3 doses); and 1.5 mg/kg in the weekly x 4 (4 doses) schedules, respectively. Furthermore, FL118 only had limited antitumor activity in the Tween 80-containing formula via the daily x 5 and the q2 x 3 schedules. In contrast to the outcomes above, the MTD for FL118 formulated in the Tween 80-free and i.v. routes-compatible formula increases 3-8 times as compared with the Tween 80-containing formula via the i.p. route administration of the drug. Specifically, the MTD of FL118 in turn reached 1.5 mg/kg, 1.5-2 mg/kg and 5 mg/kg for daily x 5, the every other day x 5 (q2 x 5, on day 0, 2, 4, 6, 8 for 5 doses), and weekly x 4 schedules, respectively. More importantly, FL118 showed highly effective antitumor activity in all the three clinical compatible schedules with i.v. administration of FL118 formulated in the new formula, while the toxicity profile appears to be improved in comparison with the outcome of FL118 formulated in the Tween 80-containing formula. FL118 effectively inhibits tumor growth, induces tumor regression and even achieved cures in a significant percentage of human xenograft tumor-bearing mice against both human colon and head-&-neck xenografts, while the tumors in control mice without FL118 treatment reached the maximal size (∼2000 mg/mm3) allowed by our protocol in less than three weeks. These findings indicate that we have developed a clinical suitable formula for i.v. administration of FL118. This would facilitate FL118 further development toward clinical trials to validate its superior antitumor efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2787. doi:1538-7445.AM2012-2787