On the other hand, we should restrict this ‘revision’ of the design approach to those drugs with a known targeted population (and so apply a ‘targeted-design’), and do not discard the traditional way for drugs without a clear beneficial patient’ group (and so apply an ‘untargeted-design’). The metastatic breast cancer scenario do offer both options: the trastuzumab and the bevacizumab registration trials [5, 6]. Trastuzumab entered the market thanks to a relatively small

trial (469 patients), while able to determine a huge survival difference (5 months); if a traditional untargeted design would have been adopted, considering a 20–30% Belinostat concentration prevalence of the HER-2 positive population, and a treatment effect of 10% benefit, more than 23 thousands of patients would have been required [7]! Conversely, although the untargeted approach used for bevacizumab allowed to register the drug with a significant (while absolutely small) benefit in progression-free

survival, retrospective evidences are emerging indicating those subset of patients where the benefit is maximized, on the basis of genetic variants [8]. The role of ‘early phases’: are traditional Selleckchem Semaxanib phase I studies with new drugs reliable? Traditional phase I studies for chemotherapeutic agents are designed to find the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of the drugs. The assumptions underlying phase I designs are that for most cytotoxic agents there is a direct relationship between the dose of a drug, its antitumor effect and toxicity. Therefore, toxicity and activity increase with the Mizoribine concentration increasing of the dose of the drug and there is a recommended

dose that provides clinical activity with acceptable toxicity. Thus, toxicity has been seen as a surrogate for potentially effective doses. With biological agents, acting on highly specific targets expressed in cancer cells, the MTD may not be reached if the drug has a much wider therapeutic ratio: therefore, an increase of the doses to toxic levels may be not necessary to achieve the maximum activity and it may be an irrelevant Edoxaban end point. There are alternative end points for these agents that can be usefully employed in phase I studies: the identification of a molecular drug effect (the ‘target effect’), the measurement of ‘surrogates’ for biological activity and the assessment of drug plasma levels. The identification of the ‘target effect’ through pharmacodynamic assays is proof of principle and can be proof of activity of the drug. The main application of pharmacodynamic studies is to help in the selection of the minimum target inhibiting dose (MTID) and the optimal schedule of administration of a drug [9].