This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The majority of clinically effective anticancer chemotherapeutic agents achieve their pharmacologic effects by relatively non-selective deoxyribonucleic acid (DNA) damage of both tumor and normal tissue cells. The DNA damage involves single and double strand breaks as well as interference with the function of DNA replication forks (replication stress). DNA damage typically evokes cellular responses to allow cell repair. A well-described key component of repair is the activation of two checkpoint kinases (Chk1 and Chk2). AZD7762 is a potent, novel and relatively selective inhibitor of Chk1 and Chk2 kinases that binds reversibly in the Chk1 adenosine 5'-triphosphate (ATP) binding pocket and inactivates Chk1 (inhibitory constant (Ki) = 3.6 nM; <10 fold selectivity over a limited number of kinases). In combination with DNA damaging agents, the compound inhibits tumor cell growth in vitro with a mode of action that correlates with Chk1 inhibition and abrogation of the G2- and S-phase checkpoints. AZD7762 has been profiled extensively and has been shown to increase the response to multiple DNAdamaging agents (eg, gemcitabine, irinotecan and doxorubicin) in a number of different cancer cell lines. AZD7762 is active in in vivo assays where inhibition of Chk1 results in the abrogation of DNA damage-induced cell cycle arrest. A clear relationship between drug exposure and checkpoint abrogation has been established in the PD model, and this data has been used to predict an efficacious dose range in man of 11 to 30 mg/m2 although significant abrogation of the checkpoint was observed at doses as low as 6 mg/m2. AZD7762 potentiates gemcitabine and irinotecan in a number of human tumor xenograft models at well-tolerated doses. This study will be the first time AZD7762 is administered to man. Safety, PK, and biomarker data in this Phase I study will support the determination of the dose(s) of AZD7762 to be evaluated in future studies. The initial clinical program for AZD7762 is designed to provide single agent AZD7762 safety and PK data. It will also provide safety, pharmacology, and tumor PD and response data in combination with gemcitabine. Since all AEs in pre-clinical species were evident in the first week and AZD7762 is intended to be dosed once weekly with gemcitabine, in this study AZD7762 will be administered on two successive weeks as a single agent (followed by a 7- day observation period after the second dose); subsequently AZD7762 will be administered following gemcitabine. Doses of AZD7762 will escalate until dose limiting toxicity or the pharmacokinetically defined endpoint is reached. Then, an additional cohort of patients at a selected dose (MTD from the dose escalation phase or lower), will be enrolled to obtain more safety, PK, and tumor response data, as well as tumor and surrogate tissue biopsies (for PD analyses of pChk1 and pH2AX).
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