Background
BET inhibitors have been tested in several clinical trials where, despite encouraging preclinical
Conclusions
BI 894999 holds significant potential as a combination drug and CCS1477 p300/CBP inhibitor is a promising partner for future clinical trials.
Methods
BRD-NUT fusions are oncogenic drivers in NUT carcinoma (NC). The effects of BI 894999 on proliferation, chromatin binding and pathway modulation were studied in NC in vitro. These studies were complemented by efficacy studies either as a single agent or in combination with the clinical p300/CBP inhibitor CCS1477.
Results
Based on the modelling of preclinical and clinical data, we proposed and implemented a new clinical scheduling regimen. This led to plasma levels sufficient to fully dislodge BRD-NUT from chromatin and to sustained and pronounced pharmacodynamic (PD) modulation of HEXIM1 and HIST2H2BF. Platelet counts in patient blood samples were improved compared to previous schedules. Rational combination studies of BI 894999 performed at clinically meaningful concentrations led to tumour regressions in all NC xenograft models tested. Conclusions: BI 894999 holds significant potential as a combination drug and CCS1477 p300/CBP inhibitor is a promising partner for future clinical trials.