RAIT of Pancreatic Cancer with Humanized PAM4

人源化 PAM4 的胰腺癌 RAIT

• 批准号: 6682139
• 负责人: Robert M Sharkey
• 金额: $ 62.49万
• 依托单位: CTR FOR MOLECULAR MEDICINE/IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6682139
• 关键词: adult human (21+); antigen antibody reaction; autoradiography; clinical research; clinical trial phase I; dosage; drug screening /evaluation; human genetic material tag; human subject; human therapy evaluation; immunoconjugates; immunoglobulin G; immunologic substance development /preparation; indium; intravenous administration; monoclonal antibody; mucins; neoplasm /cancer pharmacology; neoplasm /cancer radioimmunotherapy; pancreas neoplasms; patient oriented research; pharmacokinetics; radionuclides; tumor antigens; yttrium

DESCRIPTION (provided by applicant): The primary aim of this proposal is to initiate a Phase I clinical trial that will explore the safety and possible efficacy of a single intravenous injection of 90Y-humanized PAM4 IgG in pancreatic cancer patients. PAM4 is a monoclonal antibody directed against a unique epitope found on the human tumor-associated antigen, MUC1 that is well expressed in pancreatic cancer. The antibody does not react with normal pancreas and has limited reactivity with pancreatitis. Preclinical studies have shown that radiolabeled PAM4 is targeted to a high degree to pancreatic tumor xenografts, and 90Y-PAM4 is a highly effective therapeutic agent in these models. Very importantly, these preclinical studies show that 90Y-PAM4 can be combined with gemcitabine, the only FDA-approved chemotherapeutic agent for pancreatic cancer, to improve the therapeutic response of gemcitabine. Indeed, once this trial is completed, our primary objective will be to develop a treatment strategy for adding 90Y-hPAM4 to a standard gemcitabine treatment regimen. PAM4 has been humanized and this proposal is designed to initiate clinical studies with this antibody, radiolabeled with 111In for use in external scintigraphy as a surrogate for 90Y-hPAM4 that will be used in therapy. The clinical trial will be initiated within 6 months of funding, allowing time to complete the Points to Consider and obtain an IND. The trial is designed to first test a suitable protein dose for hPAM4 to be used in the next step of clinical testing, namely a determination of the maximum tolerated dose for 90Y-hPAM4. All patients will have a pre-therapy imaging/pharmacokinetic/dosimetry study performed with 111In-hPAM4 IgG. This study will be used to predict the behavior of the 90Y-hPAM4 IgG that will be given one-week later. All patients will be treated with 9xY-hPAM4 IgG, but in the first step, the 90Y-hPAM4 IgG will be fixed at a dose of 10 mCi/m2. Three dose cohorts are planned in the first step at 5 mg, 15 mg/m2 and 50 mg/m2. Once a suitable protein dose is selected, in the second step, escalation of the 90Y-hPAM4 radioactivity will proceed, starting at 15 mCi/m2 and escalating in 5 mCi/m2 increments until the MTD is determined. The trial design reflects early discussions with the FDA concerning an appropriate trial design for a new antibody. The trial will be conducted at the Garden State Cancer Center and Johns Hopkins University School of Medicine. CMMI will be responsible for monitoring the study's progress.

描述（由申请人提供）：该提案的主要目的是启动I期临床试验，该试验将探讨单次静脉注射90Y人性化的PAM4 IgG在胰腺癌患者中的安全性和可能的​​功效。 PAM4是一种针对人类肿瘤相关的抗原MUC1的独特表位的单克隆抗体，在胰腺癌中表达很好。该抗体与正常胰腺反应，对胰腺炎的反应性有限。临床前研究表明，放射性标记的PAM4高度针对胰腺肿瘤异种移植物，而90Y-PAM4是这些模型中高效的治疗剂。非常重要的是，这些临床前研究表明，90Y-PAM4可以与吉西他滨（吉西他滨）（胰腺癌唯一改善吉西他滨治疗反应的唯一的胰腺癌化学治疗剂。确实，一旦该试验完成，我们的主要目标将是制定一种将90Y-HPAM4添加到标准的吉西他滨治疗方案中的治疗策略。 PAM4已被人性化，该提案旨在通过该抗体进行临床研究，该抗体用111in标记为外部闪烁显像术作为90Y-HPAM4的替代物，用于治疗。临床试验将在资金的6个月内开始，从而使时间完成考虑并获得IND的积分。该试验旨在首先测试适合HPAM4的合适蛋白质剂量，用于在临床测试的下一步中使用，即确定90Y-HPAM4的最大耐受剂量。所有患者均将对使用111in-HPAM4 IgG进行的疗法前成像/药代动力学/剂量学研究。这项研究将用于预测一周后将给出的90Y-HPAM4 IgG的行为。所有患者将接受9X-HPAM4 IgG治疗，但在第一步中，90Y-HPAM4 IgG将以10 mci/m2的剂量固定。计划在5 mg，15 mg/m2和50 mg/m2的第一步中进行三个剂量队列。一旦选择了合适的蛋白质剂量，在第二步中，将继续进行90Y-HPAM4放射性的升级，从15 mci/m2开始，并以5 mci/m2增量升级，直到确定MTD。试验设计反映了与FDA有关新抗体的适当试验设计的早期讨论。该试验将在花园州癌症中心和约翰·霍普金斯大学医学院进行。 CMMI将负责监视研究的进度。