Abstract 3096: Mechanisms of synergy of carboplatin and an EphA2-targeted docetaxel antibody-directed nanotherapeutic
Authors: Kamoun Walid S. , Sawyer Andrew J. , Pien Christine , Koshkaryev Alexander , Luus Lia , Merrigan Samantha , Sun Gang , Kozin Sergey , Huang Zhaohua Richard , Tipparaju Suresh K. , Kirpotin Dmitri B. , Xu Hannah , Askoxylakis Vasileios , Reynolds Patrick C. , Drummond Daryl C. 
Published: July 2017

Abstract
Platinum-taxane combinations are widely used to treat solid tumors either in first or later lines of therapy. While effective in many settings, platinum-taxane combinatorial regimens are limited by toxicities. We have recently developed an antibody directed nanotherapeutic (MM-310) encapsulating a docetaxel prodrug, targeted to Ephrin receptor A2 (EphA2). Preclinical investigation of MM-310 revealed that the liposomal formulation leads to prolonged docetaxel exposure of the tumor with decreased exposure of normal tissues leading to a shift in toxicity profile and potentially enabling more safe and effective combinations with platinum-based chemotherapeutics. In this study, we evaluated the activity of MM-310 in combination with carboplatin in several xenograft tumor models and compared it to the activity of free docetaxel in combination with carboplatin at equitoxic dosing. Tolerability of MM-310 in combination with carboplatin in mice was evaluated, including assessing hepatotoxicity. Biodistribution, microdistribution, in vivo tumor growth, and mouse survival studies were performed in lung and ovarian cell line-derived (CDX) and patient-derived xenograft (PDX) models. MM-310 in combination with carboplatin was found to be well tolerated, enabling dosing of both drugs at high doses with maximum tolerability when the drugs were dosed three days apart. Carboplatin increased nanotherapeutic delivery to the tumor in a CDX model of triple negative breast cancer and in a PDX model of ovarian cancer. In vivo studies in lung and ovarian cancer xenograft models showed significant synergy between MM-310 and carboplatin when compared to the monotherapies, as well as when compared to free docetaxel with carboplatin, leading to a significant increase in tumor growth delay and survival (docetaxel/ carboplatin vs. MM-310/carboplatin, 0 vs 50% complete tumor regression, 24 vs 80 days median time to regrowth). Additionally, in the same studies, MM-310 and carboplatin was better tolerated than free docetaxel and carboplatin. In conclusion, we found that MM-310 in combination with carboplatin was significantly better tolerated and more effective than free docetaxel in combination with carboplatin. Mechanistically, the synergistic anti-tumor activity of MM-310 with carboplatin may be partially due to a carboplatin mediated enhancement of nanotherapeutic delivery. The increased preclinical activity of the MM-310/carboplatin combination, together with the high tolerability following scheduling optimization tested in mice, makes this combination a promising regimen that warrants evaluation in clinical trials.
Citation Format: Walid S. Kamoun, Andrew J. Sawyer, Christine Pien, Alexander Koshkaryev, Lia Luus, Samantha Merrigan, Gang Sun, Sergey Kozin, Zhaohua Richard Huang, Suresh K. Tipparaju, Dmitri B. Kirpotin, Hannah Xu, Vasileios Askoxylakis, Patrick C. Reynolds, Daryl C. Drummond. Mechanisms of synergy of carboplatin and an EphA2-targeted docetaxel antibody-directed nanotherapeutic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3096. doi:10.1158/1538-7445.AM2017-3096