RAIT of Pancreatic Cancer with Humanized PAM4

描述（由申请人提供）：本提案的主要目的是启动一项I期临床试验，该试验将探索胰腺癌患者单次静脉注射90 Y-人源化PAM 4 IgG的安全性和可能的疗效。PAM 4是一种针对人肿瘤相关抗原MUC 1上发现的独特表位的单克隆抗体，MUC 1在胰腺癌中充分表达。该抗体不与正常胰腺反应，与胰腺炎的反应性有限。临床前研究表明，放射性标记的PAM 4在很大程度上靶向胰腺肿瘤异种移植物，90 Y-PAM 4在这些模型中是一种非常有效的治疗剂。非常重要的是，这些临床前研究表明，90 Y-PAM 4可以与吉西他滨（唯一FDA批准的胰腺癌化疗药物）联合使用，以改善吉西他滨的治疗反应。事实上，一旦该试验完成，我们的主要目标将是开发将90 Y-hPAM 4添加到标准吉西他滨治疗方案中的治疗策略。PAM 4已经被人源化，并且该提议被设计用于启动使用该抗体的临床研究，该抗体用111 In放射性标记，用于外部放射性造影术，作为将用于治疗的90 Y-hPAM 4的替代物。该临床试验将在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hPAM 4的合适蛋白剂量，以用于下一步临床测试，即确定90 Y-hPAM 4的最大耐受剂量。所有患者将接受111 In-hPAM 4 IgG治疗前成像/药代动力学/剂量测定研究。本研究将用于预测一周后给予的90 Y-hPAM 4 IgG的行为。所有患者将用9 xY-hPAM 4 IgG治疗，但在第一步中，90 Y-hPAM 4 IgG将固定在10 mCi/m2的剂量。在第一步中计划了3个剂量队列，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，90 Y-hPAM 4放射性的递增将继续进行，从15 mCi/m2开始，以5 mCi/m2的增量递增，直到确定MTD。试验设计反映了与FDA就新抗体的适当试验设计进行的早期讨论。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将负责监测研究进展。

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.