RAIT of Pancreatic Cancer with Humanized PAM4

描述（由申请人提供）：本申请的主要目的是启动一项I期临床试验，以探索胰腺癌患者单次静脉注射90y人源化PAM4 IgG的安全性和可能的有效性。PAM4是一种针对人类肿瘤相关抗原MUC1上发现的独特表位的单克隆抗体，MUC1在胰腺癌中表达良好。该抗体对正常胰腺无反应，对胰腺炎反应有限。临床前研究表明，放射标记的PAM4对胰腺肿瘤异种移植物具有高度靶向性，90Y-PAM4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，90Y-PAM4可以与唯一获fda批准的胰腺癌化疗药物吉西他滨联合，提高吉西他滨的治疗效果。事实上，一旦这项试验完成，我们的主要目标将是开发一种治疗策略，将90Y-hPAM4添加到标准的吉西他滨治疗方案中。PAM4已被人源化，该提案旨在启动该抗体的临床研究，该抗体用111In放射标记，用于外部显像，作为90Y-hPAM4的替代品，将用于治疗。该临床试验将在获得资金后的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的合适蛋白剂量，以便在下一步临床试验中使用，即确定90Y-hPAM4的最大耐受剂量。所有患者都将使用111In-hPAM4 IgG进行治疗前成像/药代动力学/剂量学研究。这项研究将用于预测一周后给予的90Y-hPAM4 IgG的行为。所有患者都将接受9y - hpam4 IgG治疗，但在第一步，90Y-hPAM4 IgG将以10 mCi/m2的剂量固定。第一步计划在5mg、15mg /m2和50mg /m2三个剂量组。一旦选择了合适的蛋白质剂量，在第二步中，90Y-hPAM4的放射性将继续增加，从15 mCi/m2开始，以5 mCi/m2递增，直到确定MTD。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将负责监测研究的进展。

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.