Phase 1 Study of ABC294640 for the Treatment of Pancreatic Cancer

描述(由申请人提供)： 大量研究表明，鞘磷脂代谢在调节肿瘤细胞增殖和凋亡以及宿主炎症和血管生成过程中起着关键作用。具体地说，鞘氨酸激酶(SK)是神经酰胺/鞘氨醇1-磷酸变阻器的关键调节器，被认为控制肿瘤细胞增殖和凋亡之间的平衡。RAS诱导的癌变以及宿主的炎症反应都需要通过SK进行信号传递。由于RAS在胰腺癌中经常发生突变，而且炎症(即慢性胰腺炎)是胰腺癌的公认危险因素，鞘磷脂信号在胰腺癌中可能具有特别重要的作用。因此，抑制鞘脂信号可能为治疗胰腺癌提供了一种独特的、多靶点的机制。赞助商开发了第一批SK的非脂类抑制剂，并对其在多种癌症和炎症性疾病模型中的生物学和治疗活性进行了广泛的研究。该系列的第一个临床化合物ABC294640是一种口服的鞘氨醇激酶-2(SK2)选择性抑制剂，可通过Ras-Raf-MEK-ERK途径减弱信号，促进肿瘤细胞杀伤，并抑制宿主血管生成和炎症。此外，ABC294640与吉西他滨或紫杉醇在体外具有协同细胞毒性，在体内可增强抗肿瘤作用。因此，研究人员推测，ABC294640将通过对肿瘤细胞和宿主免疫过程的影响而具有显著的抗胰腺癌活性。作为开发ABC294640作为治疗胰腺癌新药的第一步，该项目的目标是进行该药物的第一阶段临床研究。这将是一项开放标签、剂量递增、安全性、药代动力学和药效学的ABC294640在晚期实体肿瘤患者中每天口服两次的研究。这项研究的主要目标将是确定ABC294640的最大耐受量(MTD)和剂量限制毒性；确定ABC294640在未来第二阶段方案中的推荐剂量；以及确定ABC294640的药代动力学。次要目标将是确定ABC294640治疗对药效标记物-血浆鞘氨醇1-磷酸(S1P)水平的影响，并通过客观的放射评估观察患者是否有任何ABC294640抗肿瘤活性的证据。多达33名患者将参加这项研究的剂量升级阶段。此外，一旦MTD已经建立，多达12名额外的胰腺癌患者可能被纳入MTD剂量水平，以确认在这一人群中的安全性。

DESCRIPTION (provided by applicant): A large body of research has demonstrated that sphingolipid metabolism plays a key role in the regulation of tumor cell proliferation and apoptosis, as well as host inflammatory and angiogenic processes. In particular, sphingosine kinase (SK) is a critical regulator of the ceramide /sphingosine 1-phosphate rheostat that is thought to control the balance between tumor cell proliferation and apoptosis. Signaling through SK is required for Ras-induced carcinogenesis, as well as host inflammatory responses. Because Ras is frequently mutated in pancreatic cancer, and because inflammation (i.e. chronic pancreatitis) is an established risk factor for pancreatic cancer, sphingolipid signaling may be of particular importance in this disease. Therefore, inhibition of sphingolipid signaling may provide a unique, multifocal mechanism for treating pancreatic cancer. The sponsor has developed the first non-lipid inhibitors of SK, and has conducted extensive studies of their biological and therapeutic activities in multiple models of cancer and inflammatory diseases. The first clinical compound in this series, ABC294640, is an orally-available selective inhibitor of sphingosine kinase-2 (SK2) that attenuates signaling through the Ras-Raf-MEK-ERK pathway, promotes tumor cell killing, and inhibits host angiogenesis and inflammation. Additionally, combinations of ABC294640 with gemcitabine or paclitaxel result in synergistic cytotoxicity in vitro and enhanced antitumor effects in vivo. Therefore, the investigators hypothesize that ABC294640 will have significant activity against pancreatic cancer through its effects on tumor cells and host immunologic processes. As the first step toward the development of ABC294640 as a new drug for pancreatic cancer, the goal of this project is to conduct the first-in-human, Phase 1 clinical study of this agent. This will be an open-label, dose escalation, safety, pharmacokinetic and pharmacodynamic study of ABC294640 given orally twice a day in patients with advanced solid tumors. The primary objectives of the study will be to determine the maximum tolerated dose (MTD) and the dose limiting toxicities of ABC294640; to establish the dose of ABC294640 recommended for future Phase 2 protocols; and to determine the pharmacokinetics of ABC294640. The secondary objectives will be to determine the effects of ABC294640-treatment on the pharmacodynamic marker, plasma sphingosine 1-phosphate (S1P) levels, and to observe patients for any evidence of antitumor activity of ABC294640 by objective radiographic assessment. Up to 33 patients will be enrolled in the dose-escalation phase of the study. In addition, once the MTD has been established, up to 12 additional patients with pancreatic cancer may be enrolled at the MTD dose level to confirm safety in this population.