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

人源化抗 Trop2-SN-38 缀合物治疗晚期胰腺癌

基本信息

批准号：
8392793
负责人：
William A. Wegener
金额：
$ 22.7万
依托单位：
IMMUNOMEDICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-17 至 2014-09-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8392793
关键词：
90Y Acceleration Animal Model Antibodies Antibody Specificity Antigens Clinical Trials Coupled Data Disease Dose Dose-Limiting Drug Kinetics Enrollment Epithelial Future Glycoproteins Goals Human Immunoglobulin G In complete remission Label Lysosomes Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of pancreas Malignant neoplasm of prostate Maximum Tolerated Dose Measures Medical center Monitor Monkeys Mucins Oceans Outcome Pancreas Pancreatic carcinoma Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Play Preclinical Testing Process Prodrugs Quality of life Radioimmunoconjugate Radioimmunotherapy Recovery Refractory Regimen Role SN-38 Safety Small Business Innovation Research Grant Solid Neoplasm Stable Disease Staging Supervision Testing Therapeutic Topoisomerase-I Inhibitor Toxic effect Toxicology Xenograft procedure chemotherapy clinical lot clinical research site cohort design disorder control experience gemcitabine human TACSTD2 protein humanized antibody immunogenicity improved innovation interest irinotecan malignant breast neoplasm man partial response phase 1 study pre-clinical preclinical study programs protocol development research clinical testing response standard care therapeutic development therapeutic target treatment program tumor

项目摘要

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.

描述（由申请人提供）：该 I 期 SBIR 申请的主要目标是利用由针对上皮糖蛋白-1 的人源化抗体 (hRS7) 组成的新型抗体药物偶联物 (ADC) 进行首次人体研究抗原（EGP-1，也称为 TROP-2）与伊立替康的活性拓扑异构酶 I 抑制剂 SN-38 偶联。 TROP-2 在许多不同类型的上皮癌中大量表达，并且在某些情况下，它以更具侵袭性的形式存在。 hRS7 ADC 的临床前测试表明，它在无毒剂量下可有效对抗多种人类异种移植物。作为首次人体试验，我们计划评估其在晚期胰腺癌中的活性，因为临床前数据表明该药物可以与 90Y 标记的抗胰腺粘蛋白 IgG 安全地结合使用，该 IgG 目前正在完成 II 期测试，令人鼓舞。抗肿瘤活性。因此，我们的长期目标之一是建立一个将放射免疫疗法与ADC相结合的胰腺癌综合治疗方案。然而，如果在胰腺癌的 I 期研究中证明 hRS7-SN-38 是安全的，则可以在其他癌症（如乳腺癌、卵巢癌、前列腺癌和肺癌）中测试 hRS7-SN-38。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，并与 FDA 就方案开发进行了 IND 前讨论。因此，这一 I 期申请的目标是完成一项剂量递增试验，以确定 hRS7 ADC 在既往治疗失败的 III/IV 期胰腺癌患者中的最大耐受剂量或生物活性剂量。我们预计将需要大约 5 组患者，从剂量加速设计开始，允许每组 1 名患者入组，直到我们观察到与测试物品直接相关的 2 级毒性，然后继续使用标准 3+ 3 I 期设计直至发生剂量限制性毒性。两到三个临床中心将参与该试验，因此应在发现后的第一年内完成应计，以评估 ADC 的安全性、有效性和免疫原性。我们希望，一旦完成这些评估，将提交 II 期 SBIR 申请，以便我们能够在选定的剂量方案下继续进行 Simon 2 阶段 II 期设计，以获得额外的安全性和有效性数据，使我们能够确定该试剂单独的活性。公共健康相关性：本申请旨在对一种新型抗体药物偶联物 (ADC) 进行首次人体临床测试，该抗体在无毒剂量下对多种类型的上皮癌具有良好的活性。该试验将重点关注其在晚期转移性胰腺癌患者中的使用，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。该 ADC 对许多癌症具有广泛的特异性，这意味着其在胰腺癌中的成功测试可以应用于这些其他适应症。此外，临床前测试已经表明，该药物与放射性标记抗体结合使用时，可以增强总体反应而不增加毒性，使其成为治疗实体瘤的用途广泛且前景广阔的药物。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（23）

First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors.

DOI：
10.1158/1078-0432.ccr-14-3321
发表时间：
2015-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Starodub AN;Ocean AJ;Shah MA;Guarino MJ;Picozzi VJ Jr;Vahdat LT;Thomas SS;Govindan SV;Maliakal PP;Wegener WA;Hamburger SA;Sharkey RM;Goldenberg DM
通讯作者：
Goldenberg DM