Bromodomain inhibitor OTX015 (MK-8628) combined with targeted agents shows strong in vivo antitumor activity in lymphoma

Abstract

The bromodomain inhibitor OTX015 (MK-8628) has shown anti-lymphoma activity as a single agent in both the preclinical and clinical settings, as well as in vitro synergism with several anticancer agents. Here, we report in vivo data for OTX015 in combination with the histone deacetylase inhibitor vorinostat, the Bruton's tyrosine kinase inhibitor ibrutinib, the anti-CD20 monoclonal antibody rituximab, and the mTOR inhibitor everolimus in a diffuse large B cell lymphoma model. The antitumor effect of OTX015-containing combinations in SU-DHL-2 xenografts in mice was much stronger than the activity of the corresponding single agents with almost complete tumor eradication for all four combinations. Pharmacokinetic analyses showed similar OTX015 levels in plasma and tumor samples of approximately 1.5 μM, which is equivalent to the concentration showing strong in vitro activity. For all four combinations, mean terminal levels of the bromodomain inhibitor differed from those in mice exposed to single agent OTX015, indicating a need for thorough pharmacokinetic investigations in phase I combination studies. In conclusion, our results provide a strong rationale to explore OTX015-containing combinations in the clinical lymphoma setting.

Keywords: BET inhibitor; everolimus; ibrutinib; rituximab; vorinostat.

Figure 1. In vivo treatment of ABC-DLBCL SU-DHL-2 xenografts with OTX015 as a single agent and in combination with other targeted drugs

A. Changes in tumor volumes during treatment: Black, vehicle (control mice); Blue; single agent OTX015; Red, single agent targeted drug; Green, OTX015/targeted drug combination. B. Boxplots showing percentage of tumor necrosis at the end of treatment. In each boxplot, the line in the middle of the box represents the median and the box extends from the 25th to the 75th percentile (interquartile range). * P < 0.05 when compared with control (CTR) mice. C. Histopathological analysis revealed control mice or treated only with rituximab displayed vital cell with a diffuse growth pattern (upper and lower left); addition of OTX015 was associated with large areas of coagulative necrosis (Haematoxyln and Eosin, 200X).

Figure 2. OTX015 levels in plasma and tumor tissue of SUDHL2-tumor bearing mice as a single agent or in combination with other agents

A. Plasma and B. tissue levels of OTX015 (oral 50 mg/kg/day) were measured after 5 weeks treatment, 4 h after the last OTX015 administration. Each bar represents the mean ± standard deviation.