Abstract B223: NKP-1339 synergistic activity in both in vitro and in vivo preclinical models highlights the therapeutic opportunity for NKP-1339 combination trials with a broad range of antitumor agents.

Abstract Background: NKP-1339 is a novel transferrin targeted ruthenium based compound that has shown promising single agent anti-cancer activity in preclinical models and in man. The compound has a novel mechanism of action, with GRP78 down-regulation included in its target pathways. In an ongoing Phase I study, the side effects are all mild and do not include those associated with standard cytotoxics or targeted agents, suggesting that NKP-1339 could be safely combined with standard anticancer therapies. The aim of this study was to evaluate the anti-tumor effects of NKP-1339 combination with these agents. Methods: In vitro combination studies were performed in breast, colon, lung, gastric, prostate, pancreatic and liver tumor cell lines with cisplatin, oxaliplatin, 5-FU, docetaxel, doxorubicin, gemcitabine, erlotinib or sorafenib as appropriate for that tumor type. Cells were exposed to NKP-1339 and a combination agent, both agents at their respective ED50, for 72hrs. Cytotoxicity was determined using the MTT assay and combination index (CI) values were calculated using the Chou-Talalay method. The effect of the NKP-1339 and cisplatin combination was further studied in vivo in a gastric carcinoma xenograft model. Results: The in vitro combination studies demonstrated NKP-1339 synergism with other anti-cancer agents in varied tumor types. The CI values ranged from 0.8 (synergism) to 0.1 (strong synergism): cisplatin (CI 0.1), doxorubicin (CI 0.2), 5-FU (CI 0.3), oxaliplatin (CI 0.4), sorafenib (CI 0.5), docetaxel (CI 0.5), erlotinib (CI 0.6), gemcitabine (0.8). In vivo studies on the combination of NKP-1339 and cisplatin in gastric carcinoma xenografts showed significant (P<0.05) tumor growth delay and extended survival when compared to the single agent activity for either compound. Conclusions: NKP-1339's novel mechanism of action and its favorable safety profile in humans suggest that it could be safely combined with standard anti-cancer therapies. The marked synergistic effects of NKP-1339 in combination with a broad range of anti-tumor agents in vitro and in vivo supports the study of this novel agent with standard anticancer therapies in Phase I combination clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B223.