RAIT of Pancreatic Cancer with Humanized PAM4

人源化 PAM4 的胰腺癌 RAIT

• 批准号: 6776902
• 负责人: Robert M Sharkey
• 金额: $ 86.69万
• 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/6776902
• 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一项 I 期临床试验，探索胰腺癌患者单次静脉注射 90Y 人源化 PAM4 IgG 的安全性和可能的​​疗效。 PAM4 是一种单克隆抗体，针对人类肿瘤相关抗原 MUC1 上发现的独特表位，MUC1 在胰腺癌中良好表达。该抗体不与正常胰腺发生反应，对胰腺炎的反应也有限。临床前研究表明，放射性标记的 PAM4 高度靶向胰腺肿瘤异种移植物，并且 90Y-PAM4 在这些模型中是一种高效的治疗剂。非常重要的是，这些临床前研究表明，90Y-PAM4可以与FDA唯一批准的胰腺癌化疗药物吉西他滨联合使用，以提高吉西他滨的治疗反应。事实上，一旦这项试验完成，我们的主要目标将是制定一种治疗策略，将 90Y-hPAM4 添加到标准吉西他滨治疗方案中。 PAM4 已人源化，该提案旨在启动该抗体的临床研究，该抗体用 111In 放射性标记，用于外部闪烁扫描，作为将用于治疗的 90Y-hPAM4 的替代品。临床试验将在资助后 6 个月内启动，以便有时间完成考虑要点并获得 IND。该试验旨在首先测试 hPAM4 的合适蛋白质剂量，用于下一步的临床测试，即确定 90Y-hPAM4 的最大耐受剂量。所有患者都将接受 111In-hPAM4 IgG 的治疗前成像/药代动力学/剂量测定研究。这项研究将用于预测一周后给予的 90Y-hPAM4 IgG 的行为。所有患者都将接受 9xY-hPAM4 IgG 治疗，但第一步，90Y-hPAM4 IgG 将固定在 10 mCi/m2 的剂量。第一步计划三个剂量组，分别为 5 mg、15 mg/m2 和 50 mg/m2。一旦选择了合适的蛋白质剂量，在第二步中，90Y-hPAM4 放射性将继续升级，从 15 mCi/m2 开始，以 5 mCi/m2 增量升级，直到确定 MTD。该试验设计反映了与 FDA 关于新抗体适当试验设计的早期讨论。该试验将在花园州立癌症中心和约翰霍普金斯大学医学院进行。 CMMI 将负责监控研究进展。