This phase I trial was designed to determine the safety and maximum tolerated dose (MTD) of tipifarnib in combination with gemcitabine and cisplatin in patients with advanced solid tumours. This combination showed evidence of antitumour activity and warrants further evaluation in a phase II setting. and studies (End (1995). For cisplatin, 5?ml blood samples were obtained at 0, 1.5, 3, 3.25, 3.5, 4, 5, 6.5, 10.5 and 23?h after Rabbit polyclonal to STAT2.The protein encoded by this gene is a member of the STAT protein family.In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo-or heterodimers that translocate to the cell nucleus where they act as transcription activators.In response to interferon (IFN), this protein forms a complex with STAT1 and IFN regulatory factor family protein p48 (ISGF3G), in which this protein acts as a transactivator, but lacks the ability to bind DNA directly.Transcription adaptor P300/CBP (EP300/CREBBP) has been shown to interact specifically with this protein, which is thought to be involved in the process of blocking IFN-alpha response by adenovirus. the start of the 3?h infusion. Blood samples were immediately centrifuged for 5?min at 4C and 1500?studies are warranted to unravel the mechanism of interaction between tipifarnib and dFdU. It is expected that the magnitude of the found interaction has limited or no clinical implications. The pharmacokinetic parameters of tipifarnib were not significantly affected by the concomitant administration of gemcitabine and cisplatin. There was substantial interpatient variability in the AZD1480 IC50 pharmacokinetic data of tipifarnib, which has been AZD1480 IC50 observed in single agent phase I trials as well (Zujewski et al, 2000; Karp et al, 2001; Crul et al, 2002). The present trial demonstrated that tipifarnib in combination with gemcitabine and cisplatin is safe and that major and clinically AZD1480 IC50 relevant drugCdrug interactions were not evident. Consistent with this finding, the current regimen revealed signs of activity in a wide variety of tumours. There were eight confirmed partial responses and 12 patients remained stable for more than 8 weeks. As this study represents a combination of tipifarnib with an effective cytotoxic regimen, the promising efficacy results documented in this study also have to be interpreted with AZD1480 IC50 caution. Nonetheless, phase II studies of this combination in a number of solid tumours are warranted. It is of interest to determine if this combination has equal or greater effect than the standard treatment of gemcitabine and cisplatin alone and more information is needed about the mechanism of action AZD1480 IC50 of tipifarnib to select potential surrogate markers to determine if the recommended dose is also the effective dose. Acknowledgments This work was supported by Johnson & Johnson Pharmaceutical Research & Development (New Jersey, USA)..