0629GCC: A PHASE I, OPEN-LABEL, MULTI-CENTER, DOSE-ESCALATION STUDY TO ASSESS SL

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 大多数临床有效的抗癌化疗药物通过对肿瘤和正常组织细胞的相对非选择性脱氧核糖核酸（DNA）损伤来实现其药理作用。DNA损伤包括单链和双链断裂以及干扰DNA复制叉的功能（复制应激）。DNA损伤通常引起细胞反应以允许细胞修复。修复的一个众所周知的关键组成部分是两个检查点激酶（Chk 1和Chk 2）的激活。AZD 7762是Chk 1和Chk 2激酶的一种有效、新型和相对选择性的抑制剂，在Chk 1腺苷5 '-三磷酸（ATP）结合口袋中可逆结合并灭活Chk 1（抑制常数（Ki）= 3.6 nM;对有限数量的激酶的选择性<10倍）。与DNA损伤剂组合时，该化合物以与Chk 1抑制和G2和S期检查点消除相关的作用模式抑制体外肿瘤细胞生长。AZD 7762已被广泛描述，并已被证明在许多不同的癌细胞系中增加对多种DNA损伤剂（例如，吉西他滨、伊立替康和多柔比星）的应答。AZD 7762在体内试验中具有活性，其中Chk 1的抑制导致DNA损伤诱导的细胞周期停滞的消除。已在PD模型中确立了药物暴露与检查点废除之间的明确关系，该数据已用于预测11 - 30 mg/m2的人体有效剂量范围，尽管在低至6 mg/m2的剂量下观察到检查点的显著废除。在许多人肿瘤异种移植模型中，AZD 7762在耐受良好的剂量下增强吉西他滨和伊立替康。本研究将是AZD 7762首次用于人体。本I期研究中的安全性、PK和生物标志物数据将支持在未来研究中评估的AZD 7762剂量的确定。AZD 7762的初始临床项目旨在提供AZD 7762单药安全性和PK数据。还将提供与吉西他滨联合用药的安全性、药理学和肿瘤PD和缓解数据。由于临床前种属中的所有AE在第一周均明显，且AZD 7762预期与吉西他滨一起每周给药一次，因此在本研究中，AZD 7762将连续两周作为单药给药（第二次给药后为7天观察期）;随后AZD 7762将在吉西他滨给药后给药。AZD 7762的剂量将递增，直至达到剂量限制性毒性或药代动力学定义的终点。然后，将入组选定剂量（剂量递增阶段的MTD或更低）的额外患者队列，以获得更多安全性、PK和肿瘤缓解数据，以及肿瘤和替代组织活检（用于pChk 1和pH 2AX的PD分析）。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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).