Phase 1 Study of ABC294640 for the Treatment of Pancreatic Cancer

ABC294640治疗胰腺癌的1期研究

• 批准号: 8216986
• 负责人: LYNN W MAINES
• 金额: $ 20万
• 依托单位: APOGEE BIOTECHNOLOGY CORPORATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-06 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8216986
• 关键词: Phase; Study; ABC294640; Treatment; Pancreatic

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.

描述（由申请人提供）： 大量研究表明，鞘脂代谢在肿瘤细胞增殖和凋亡以及宿主炎症和血管生成过程的调节中起着关键作用。特别地，鞘氨醇激酶（SK）是神经酰胺/鞘氨醇1-磷酸变阻器的关键调节剂，其被认为控制肿瘤细胞增殖和凋亡之间的平衡。通过SK的信号传导是Ras诱导的致癌作用以及宿主炎症反应所必需的。因为Ras在胰腺癌中经常突变，并且因为炎症（即慢性胰腺炎）是胰腺癌的既定风险因素，所以鞘脂信号传导在这种疾病中可能特别重要。因此，抑制鞘脂信号传导可能为治疗胰腺癌提供独特的多灶性机制。申办方已开发出第一种SK非脂质抑制剂，并在多种癌症和炎性疾病模型中对其生物学和治疗活性进行了广泛研究。该系列中的第一个临床化合物ABC 294640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途径减弱信号传导，促进肿瘤细胞杀伤，并抑制宿主血管生成和炎症。此外，ABC 294640与吉西他滨或紫杉醇的组合导致体外协同细胞毒性和体内增强的抗肿瘤作用。因此，研究人员假设ABC 294640将通过其对肿瘤细胞和宿主免疫过程的影响对胰腺癌具有显著的活性。 作为开发ABC 294640作为胰腺癌新药的第一步，该项目的目标是进行该药物的首次人体I期临床研究。这是一项在晚期实体瘤患者中开展的开放标签、剂量递增、安全性、药代动力学和药效学研究，研究对象为每日两次口服给予的ABC 294640。本研究的主要目的是确定ABC 294640的最大耐受剂量（MTD）和剂量限制毒性;确定未来2期方案推荐的ABC 294640剂量;并确定ABC 294640的药代动力学。次要目的是确定ABC 294640治疗对药效学标志物血浆1-磷酸鞘氨醇（S1 P）水平的影响，并通过客观影像学评估观察患者是否存在ABC 294640抗肿瘤活性的任何证据。最多33例患者将入组研究的剂量递增阶段。此外，一旦确定了MTD，最多可在MTD剂量水平招募12例额外的胰腺癌患者，以确认该人群的安全性。