A Phase I Trial Of Mk-2206 And Hydroxychloroquine(Hcq) In Solid Tumors, Melanoma, Renal, And Prostate Cancer To Examine The Role Of Antophagy In Tomorigenesis

TPS2640 Background: AKT is a frequently hyperactivated oncogenic kinase in human cancers (Degenhardt 2006). Inhibition of AKT activates autophagy, promoting tumor survival, and hence AKT inhibitors may limit their own efficacy. HCQ inhibits autophagy and may prevent this survival mechanism. Treating renal cell carcinoma lines with temsirolimus, an mTOR inhibitor, promoted autophagy-mediated stress tolerance and the concomitant inhibition of autophagic degradation with chloroquine, enhanced tumor cell death (Bray 2012, Xie 2013). A similar phenomenon was reported with AKT inhibition (Degtyarev 2008, Cheny 2011) We hypothesize that Akt inhibition by the allosteric inhibitor MK-2206 will induce autophagy which may be inhibited by the addition of HCQ, potentially enhancing cell death and improving therapeutic outcomes. The purpose of this study is to define the maximum tolerated dose of MK-2206 and HCQ when used in combination, to determine the pharmacokinetic (PK) profile of the combination and to assess sur...