Phase I trial of the combination of bortezomib and clofarabine in adults with refractory solid tumors.

TPS2614 Background: We conducted a systematic combination drug screen across the NCI-60 cell line panel encompassing nearly all pairwise combinations of FDA-approved small-molecule cancer drugs ( u003e 5000) using multiple, clinically-achievable drug concentrations to discover efficacious combinations that could be advanced rapidly into clinical trials (Eur J. Cancer 2012 Nov;48, Suppl 6:11). The proteasome inhibitor bortezomib combined with the nucleoside inhibitor clofarabine was found to be supra-additive in multiple cell lines. Several solid tumor xenograft models were used to confirm enhanced responses to this combination than to the individual single agents at their Maximum Tolerated Doses (MTDs), with the combination displaying either prolonged tumor stasis or regression. Because both bortezomib and clofarabine have individually demonstrated to enhance tumor cell apoptosis in vitro, we investigated the role of alterations in the apoptotic pathway in producing the observed supra-additive efficacy for th...