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

描述(申请人提供)：作为一个类别，喜树碱因其治疗潜力而得到广泛认可，但由于许多原因，包括亲脂性内酯部分的不稳定，尚未完全实现。DB-67(7-叔丁基二甲基硅基-10-羟基喜树碱)是第三代类似物，在构效关系研究的基础上设计成具有稳定的血液和高效的作用。喜树碱有一个不稳定的α-羟基-5-内酯环，该环可水解生成带负电荷的羧酸盐形式。与不带电荷的内酯相比，带负电荷的羧酸盐不太可能扩散到细胞内，因此通常被认为是“不活跃的”。基于其血液稳定性和抗肿瘤活性，DB-67被NCI通过三个周期的RAID计划选择进行开发。来自NCI研究和合作努力的数据显示，在体外和体内的抗肿瘤活性令人印象深刻，特别是在胶质瘤模型中，但在黑色素瘤和结肠异种移植模型中也是如此。目前，DB-67配方和毒理学研究已经完成，临床级材料可通过NCI获得。根据在临床前模型中观察到的广泛的配方、毒理学和药代动力学特征，以及它在人类身上发挥强大的抗肿瘤作用的潜力，我们假设DB-67将在临床试验中具有良好的耐受性和有效性。这项赠款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在难治性实体肿瘤患者中的处置和毒性。将完成以下具体目标：1.1)估计DB-67的最大耐受量(MTD)，并描述DB-67静脉注射的剂量限制毒性(DLT)；DB-67每天一次，每21天静脉注射5天，对标准治疗无效的复发或难治性实体肿瘤的成人；1.2)描述DB-67静脉注射后的血浆药代动力学并与DB-67的药代动力学和毒性相关。最终，我们的目标是在一线治疗中使用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使用，目的是改善患者的整体结果。

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.