Abstract 1727: Preclinical evaluation of pan-VEGFR inhibitor tivozanib in combination with capecitabine, sirolimus or erlotinib in genetically engineered tumor models support combinations based on complementary mechanisms
Authors: Jiang Feng , Shen Luhua , Sun Xiaojian , Li Guangmu , Bressel Angela , Rideout William M. , Zhou Yinghui , Heyer Joerg , Chiu M. Isabel , Robinson Murray O. , Lin Jie 
Published: June 2012

Abstract
Tivozanib (AV-951) is a highly potent and selective VEGFR TKI that has been shown to be active in a phase 2 clinical trial in RCC, and importantly, to be combinable in phase 1b trials with temsirolimus, paclitaxel and Folfox. However, given the widely mixed clinical experience in combining anti-VEGF agents with targeted therapies or chemotherapies, it is critical to preclinically identify and evaluate optimal combinations using animal models that are relevant to human cancer and tailored to reflect clinical opportunities.
To investigate tivozanib combinations with capecitabine or sirolimus, we exploited a population based murine breast tumor model, in which, multiple primary tumors generated genetically were expanded in vivo, characterized and then stratified to represent responders or non-responders to each single agent. To ask mechanistic questions and elucidate potential synergies, in addition to pharmacological assessment, pharmacodynamic analyses were performed using histopathology and molecular markers.
Tivozanib combination with capecitabine was evaluated in tumors that exhibited limited response to capecitabine single agent at clinically relevant dose and showed insignificant tumor inhibition by tivozanib alone. Combination of the two agents resulted in tumor regression accompanied by massive necrosis. Further, this substantially increased efficacy could be achieved with reduced doses of either agent, indicating synergistic mechanisms.
In tumors where sirolimus alone blocked tumor progression without efficient tumor killing, adding tivozanib resulted in rapid and near complete tumor reduction. Importantly, while drug resistance emerged in tumors received either agents, it is not observed in the combination therapy, with evidence of both antiangiogenic and antitumor effects. In an acquired tivozanib resistance model in which either agent alone induced only partial growth inhibition, the combination resulted in tumor stasis.
We investigated tivozanib combination with erlotinib in lung tumors that acquired the EGFR TKI resistance mutation L858R/T790M spontaneously. In this study, tivozanib elicited antitumor activity but failed to block tumor progression. When combined with erlotinib, rapid tumor regression was achieved. Continued treatment resulted in prolonged total tumor suppression, evident by residual lesions upon necropsy.
These preclinical studies provided an opportunity to model clinical combinations in a context where the mechanistic contribution of each agent could be characterized. Tivozanib combined with each of the three agents, capecitabine, sirolimus or erlotinib demonstrated mechanistically complementary antitumor effect that resulted in substantially improved activity, providing support for such clinical combinations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1727. doi:10.1158/1538-7445.AM2011-1727