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The deciphering of key molecular targets and pathways cancers are addicted to ("oncogene-addiction") has led to a paradigm shift in the treatment of cancers from the "one-size-fits-all" strategy to personalized medicine that tailors therapy to molecularly defined subgroups of patients.The drug development of molecularly targeted agents (MTAs)starts with the identification of the aberrantly activated pathway and the design of compounds targeted against the specific molecular aberrations and the search for predictive biomarkers for their efficacy.MTAs promise to be more efficacious and less toxic anti-tumour therapies for cancer patients with defined molecular aberrations.On the other hand, selecting patients based on their molecular protrait may accelerate drug development, which is still slow and inefficient, and eventually even speed up regulatory drug approval.In order to achieve this goal, a new paradigm is emerging that involves the use of innovative customized clinical trial designs including enrichment strategies based on the patients molecular profile especially in the earliest stage of clinical development.Although modern phase Ⅰ trials of MTAs still aim for determining the maximum tolerated dose (MTD) and the pharmacokinetics (PK) and-dynamics (PD) of the experimental compound, they additionnally incorporate adaptive designs for analysing information regarding PD and surrogate intermediate end points and use enrichment strategies for molecularly defined patients,especially in expanded cohorts at the MTD.This strategy may allow the immediate progression from phase Ⅰ directly to randomized phase Ⅱ/Ⅲ trials, thus obviating the need for phase Ⅱ trials, as it has been shown for cabozantinib (XL184), a multi-tyrosine kinase inhibitor, in patients with medullary thyroid cancer and may even accelerate regulatory drug approval, as has been evidenced by the accelerated FDA-approval of crizotinib (PF-02341066) in patients with NSCLC who have EML4-ALK-rearrangements.As single-arm phase Ⅱ studies have often been shown to be false positive, the conduct of randomized phase Ⅱ trials is preferable;moreover, as most MTAs being cytostatic rather than eytotoxic, a time-to-event end point, e.g.progression-free survival (PFS) at a predefimed timepoint, instead of objective response rate according to RECIST as primary end point in phase Ⅱ trials of MTAs is a valid alternative.Lastly, the use of innovative settings, e.g.the neoadjuvant setting in breast cancer, is a very elegant platform to evaluate MTAs faster.The Ⅰ-SPY 2 trial for instance uses an adaptive trial design exploring various MTAs in parallel in the neoadjuvant setting according to the molecular profile of the tumor.