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

• 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
• 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

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申请的主要目的是使用一种新的抗体-药物偶联物（ADC）进行首次人体研究，该抗体-药物偶联物（ADC）由人源化抗体（hRS7）与上皮糖蛋白-1抗原（EGP-1，也称为TROP-2）偶联到SN-38（伊立替康的活性拓扑异构酶I抑制剂）组成。TROP-2在许多不同类型的上皮癌中大量表达，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，它在无毒剂量下对多种人类异种移植物有效。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安全地与90y标记的抗胰腺粘蛋白IgG联合使用，该抗体目前正在完成II期试验，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综合的胰腺癌治疗方案，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的生产和临床前评估，包括将用于提交IND的免疫组织学和猴子毒理学研究，并就方案制定与FDA进行了IND前讨论。因此，该I期申请的目标是完成一项剂量递增试验，以确定hRS7 ADC在一次治疗失败的III/IV期胰腺癌患者中的最大耐受剂量或生物活性剂量。我们预计将需要约5个患者队列，从剂量加速设计开始，允许每个队列入组1名患者，直到我们观察到与试验文章直接相关的2级毒性，然后继续使用标准的3+3 I期设计，直到剂量限制性毒性发生。两到三个临床站点将参与该试验，因此应在发现的第一年内完成累积，以评估ADC的安全性、有效性和免疫原性。我们希望，一旦这些评估完成，将提交II期SBIR申请，以便我们可以继续在选定的给药方案下进行Simon 2期II期设计，以获得额外的安全性和有效性数据，使我们能够确定该药物单独的活性。

项目成果

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
• 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