Humanized Anti-Trop2-SN-38 Conjugate For Advanced Pancreatic Cancer

描述(由申请人提供)：这项第一阶段SBIR应用的主要目标是使用一种新的抗体-药物结合物(ADC)进行第一人研究，该结合物由针对上皮糖蛋白-1抗原(EGP-1，也称为trp-2)的人源化抗体(HRS7)与伊立替康的活性拓扑异构酶I抑制剂SN-38偶联而成。TROP-2在许多不同类型的上皮性癌中大量表达，在某些情况下，它以更具侵袭性的形式存在。HRS7 ADC的临床前测试表明，它在无毒剂量下对各种人类移植瘤有效。作为第一个人的经验，我们计划评估它在晚期胰腺癌中的活性，因为临床前的数据表明，这种药物可以安全地与90Y标记的抗胰腺粘蛋白抗体结合，后者目前正在完成第二阶段测试，具有令人鼓舞的抗肿瘤活性。因此，我们的长期目标之一是建立一个全面的胰腺癌治疗计划，将放射免疫治疗与ADC相结合。然而，如果在胰腺癌的I期研究中被证明是安全的，hRS7-SN-38可以在其他癌症(如乳腺癌、卵巢癌、前列腺癌和肺癌)中进行测试。我们已经完成了hRS7-SN-38 ADC的制造和临床前评估，包括将用于提交IND的免疫组织学和猴子毒理学研究，并在IND前与FDA就方案开发进行了讨论。因此，这一第一阶段应用的目标将是完成一项剂量递增试验，以确定在先前一次治疗失败的III/IV期胰腺癌患者中hRS7 ADC的最大耐受剂量或生物学活性剂量。我们预计将需要大约5名患者，从剂量加速设计开始，允许每个队列1名患者参加，直到我们观察到与测试品直接相关的2级毒性，然后继续使用标准的3+3阶段I设计，直到发生剂量限制毒性。两到三个临床站点将参与这项试验，因此应在发现第一年内完成应计，以评估ADC的安全性、有效性和免疫原性。我们希望，一旦进行了这些评估，将提交第二阶段SBIR申请，这样我们就可以在选定的剂量方案下继续进行SIMON 2阶段第二阶段设计，以获得更多的安全性和有效性数据，使我们能够单独确定该制剂的活性。 公共卫生相关性：该应用程序寻求对一种新的抗体-药物结合物(ADC)进行首例临床测试，该结合物在许多类型的上皮性癌症中具有良好的活性，且剂量无毒。这项试验将集中在晚期转移性胰腺癌患者中使用它，进行I期剂量递增试验，以确定最大耐受剂量或生物活性剂量。这种ADC对许多癌症具有广泛的特异性，这意味着它在胰腺癌中的成功测试可以应用于这些其他适应症。此外，临床前试验已经表明，当这种药物与放射性标记抗体相结合时，可以在不增加毒性的情况下增强整体反应，使其成为治疗实体肿瘤的一种非常通用和有前景的药物。

DESCRIPTION (provided by applicant): The main objective of this Phase I SBIR application is to perform the first-in-man studies with a new antibody-drug conjugate (ADC) composed of a humanized antibody (hRS7) to the epithelial glycoprotein-1 antigen (EGP-1, also known as TROP-2) coupled to SN-38, the active topoisomerase I inhibitor from irinotecan. TROP-2 is abundantly expressed in many different types of epithelial cancer, and in some instances, it is present in the more aggressive forms. Preclinical testing of the hRS7 ADC has shown it is effective against a variety of human xenografts at non-toxic doses. As a first-in-man experience, we plan on evaluating its activity in advanced pancreatic cancer, since preclinical data have indicted this agent can be combined safely with a 90Y-labeled anti-pancreatic mucin IgG that is currently completing Phase II testing with encouraging anti-tumor activity. Thus, one of our long-term objectives is to build a comprehensive treatment program for the treatment of pancreatic cancer that will combine radioimmunotherapy with ADC. However, if proven safe in the Phase I study in pancreatic cancer, the hRS7-SN-38 could be tested in other cancers (such as breast, ovarian, prostate, and lung cancers). We have completed manufacturing and preclinical assessment of the hRS7-SN-38 ADC, including immunohistology and monkey toxicology studies that will be used to submit an IND, and had pre-IND discussions with the FDA in terms of protocol development. Thus, the goal of this Phase I application will be to complete a dose-escalation trial to determine the maximum tolerated dose or a biologically active dose of the hRS7 ADC in patients with stage III/IV pancreatic cancer who have failed one prior treatment. We expect ~5 cohorts of patients will be required, starting with a dose acceleration design that allows 1 patient per cohort to be enrolled until we observe Grade 2 toxicity that is directly relatd to the test article, and then to proceed using a standard 3+3 Phase I design until dose-limiting toxicity occurs. Two to three clinical sites will participate in this trial, and therefore accrual should be completed within the first year of finding to assess safety, efficacy and immunogenicity of the ADC. We are hopeful that once these assessments are made, a Phase II SBIR application will be filed so that we can continue to a Simon 2-stage Phase II design at a selected dosing regimen to obtain additional safety and efficacy data, enabling us to determine the activity of this agent alone. PUBLIC HEALTH RELEVANCE: This application seeks to perform first-in-man clinical testing of a new antibody-drug conjugate (ADC) that has promising activity in many types of epithelial cancer at non-toxic doses. This trial will focus on its use in patients with advanced metastatic pancreatic cancer, performing a Phase I dose-escalation trial to determine the maximum tolerated dose or a biologically active dose. The broad specificity of this ADC for many cancers means its successful testing in pancreatic cancer can be applied to these other indications. Additionally, preclinical testing has already shown this agent, when combined with a radiolabeled antibody, can enhance overall response without increasing toxicity, making this a very versatile and promising agent for the management of solid tumors.