Phase I and Biological Studies of DB67 - A Blood Stable Camptothecin

描述（由申请人提供）：作为一类，喜树碱因其治疗潜力而被广泛认可，但由于许多原因，包括亲脂性内酯部分的不稳定性，尚未完全实现。DB-67（7-叔丁基二甲基甲硅烷基-10-羟基喜树碱）是第三代类似物，其基于结构-活性关系研究被设计成血液稳定且高效。喜树碱具有不稳定的α-羟基-5-内酯环，其水解产生带负电荷的羧酸盐形式。与不带电荷的内酯相比，带负电荷的羧酸酯不太可能扩散到细胞中，并且通常被认为是“无活性的”。“基于其血液稳定性和抗肿瘤活性，DB-67被NCI选择通过RAID计划的三个周期进行开发。来自NCI研究和合作努力的数据显示了令人印象深刻的体外和体内抗肿瘤活性，特别是在神经胶质瘤模型中，但也在黑素瘤和结肠异种移植模型中。目前，DB-67的配方和毒理学研究已经完成，临床级材料可通过NCI获得。基于在临床前模型中观察到的广泛的制剂、毒理学和药代动力学特征，以及其在人体中发挥强效抗肿瘤作用的潜力，我们假设DB-67在临床试验中耐受良好且有效。该资助申请概述了临床研究和相关的药代动力学研究，这些研究将确定DB-67在难治性实体瘤患者中的分布和毒性。1.1）估计静脉内DB-67的最大耐受剂量（MTD）并描述对患有复发性或难治性实体瘤的成人的剂量限制毒性（DLT），所述DB-67每天一次给药，每21天给药5天，其中标准疗法无效; 1.2）表征静脉给药后DB-67及其代谢物的血浆药代动力学，并将DB-67的药代动力学和毒性相关。最终，目标是将DB-67作为单一药物或与其他分子靶向治疗或细胞毒性药物联合用于一线治疗，以改善患者的总体结局。

DESCRIPTION (provided by applicant): As a class, the camptothecins have been widely recognized for their therapeutic potential, which for many reasons, including the instability of the lipophilic lactone moiety, has not been fully realized. DB-67 (7-t- butyldimethylsilyl-10-hydroxycamptothecin) is a third generation analog that was engineered to be blood stable and highly potent, on the basis of structure-activity relationship studies. The camptothecins have a labile a-hydroxy-5-lactone ring, which hydrolyzes to yield the negatively charged carboxylate form. Compared to the uncharged lactone, the negatively charged carboxylate is less likely to diffuse into cells and is often considered "inactive." Based on its blood stability and anti-tumor activity, DB-67 was selected by the NCI for development through three cycles of the RAID program. Data from NCI studies and from collaborative efforts revealed impressive in vitro and in vivo anti-tumor activity, particularly in glioma models, but also in melanoma and colon xenograft models. Currently DB-67 formulation and toxicology studies have been completed and clinical grade material is available through the NCI. Based on the extensive formulation, toxicology, and pharmacokinetic profile observed in preclinical models, and its potential to exert a potent anti-tumor effect in humans, we hypothesize that DB-67 will be well-tolerated and efficacious in clinical trials. This grant application outlines the clinical studies and the correlative pharmacokinetic studies that will define DB-67 disposition and toxicity in patients with refractory solid tumors. The following specific aims will be accomplished: 1.1) To estimate the maximum tolerated dose (MTD) and describe the dose limiting toxicities (DLT) of intravenous DB-67 administered once daily for 5 days every 21 days to adults with recurrent or refractory solid tumors in which standard therapies are not effective; 1.2) To characterize the plasma pharmacokinetics of DB-67 and metabolites after intravenous administration and relate DB-67 pharmacokinetics and toxicity. Ultimately, the objective is to use DB-67 as a single agent or in combination with other molecular-targeted therapies or cytotoxics in frontline therapy with the goal to improve overall patient outcome.