MONOCLONAL ANTIBODY 81C6-I-131 METASTATIC TO LEPTOMENINGES

单克隆抗体 81C6-I-131 转移至软脑膜

• 批准号: 6243937
• 负责人: MARK T BROWN
• 金额: $ 3.24万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1975
• 资助国家: 美国
• 起止时间: 1975-10-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6243937
• 关键词: brain neoplasms; clinical research; clinical trial phase I; drug administration routes; human subject; human therapy evaluation; immunoconjugates; iodine; meningioma; metastasis; monoclonal antibody; neoplasm /cancer immunotherapy; neoplasm /cancer radionuclide therapy; radiation therapy dosage; radionuclides

This protocol contains two active components, each assigned a separate Duke IRB number, and a third component, which has been successfully completed and is now closed. The component which has been completed utilized 131Iodine-labeled 81C6 monoclonal antibody in the treatment of patients with neoplasms metastatic to the leptomeninges. The purpose of this study was to determine the safety and maximum tolerated dose of intrathecal 131I-labeled 81C6 monoclonal antibody in patients with neoplasms metastatic to the leptomeninges. In one part of this protocol, 81C6 IgG monoclonal antibody conjugated to 131I was utilized in the treatment of neoplasms metastatic to the leptomeninges or postoperative tumor cystic cavities communicating with cerebrospinal fluid. It was a phase I dose-escalation study designed to determine the toxicity profile and maximum tolerated isotope dose. The protocol began at 40 mCi 131I and escalated in 20 mCi increments (i.e., 60, 80, 100, etc. mCi) in cohorts of 3-6 patients per dose level until the maximum tolerated dose was reached. Response were assessed secondarily. The maximum tolerated 131I-81C6 dosage for a single intrathecal administration in adult patients was 80 mCi 131I-81C6 (10 mg protein). The dosage limiting toxicity was hematologic toxicity. We treated 31 patients and noted one partial response and disease stabililzation in 13 of 31 patients (42%). This portion of the protocol has been sucessfully completed, and a manuscript describing the results has been published (see attatched copy). One active component of this protocol utilizes 131I-labeled 81C6 monoclonal antibody in the treatment of patients with primary or metastatic malignant brain tumors with surgically created cystic resection cavities. The purpose of this study is to determine the safety and maximum tolerated dose of 131I-labeled 81C6 monoclonal antibody administered into surgically created cystic tumor resection cavities in patients with primary or metastatic malignant brain tumors. The second active component utilizes 131I-labeled 81C6 monoclonal antibody in the treatment of patients with recurrent cystic gliomas. The purpose of this study is to determine the safety and maximum tolerated dose of 131I-labeled 81C6 monoclonal antibody administered into naturally occurring tumor cyst cavities in patients with recurrent cystic gliomas. 81C6 IgG monoclonal antibody conjugated to 131I is utilized in the treatment of patients with recurrent cystic gliomas or patients with primary or metastatic malignant brain tumors with surgically created cystic resection cavities. These are phase I dose- escalation studies designed to determine the toxicity profile and maximum tolerated isotope dosage for each patient population above. The protocol began at 20 mCi 131I and is escalating in 20 mCi increments (i.e.40, 60, 80, 100, etc. mCi) in cohorts of 3-6 patients per dosage level until the maximum tolerated dosage is reached. Response is assessed secondarily. These studies are continuing to accrue patients. We have identified the maximum tolerated dose as 100 mCi 131I-81C6 (20 mg protein) in previously radiated patients with surgically created cystic resection cavities. This arm of the protocol has closed and a manuscript is in preparation. The other arms of the active protocol components remain open for accrual. These disease entities are all devastating, incurable neurologic complications of cancer where present treatments are inadequate. The development of monoclonal antibodies has provided the potential for more specific therapy of tumors which are reactive with the monoclonal antibody or antibody fragment. Antibodies that are specific to the tumor cells and that do not react with normal brain or spinal cord can be conjugated with therapeutic radioisotopes, such as 131I. This conjugate can then be delivered intrathecally for leptomentingeal neoplasms, into a naturally-ocurring tumor cyst cavity for cystic brain tumors, or into a surgically-created resection cavity for solid brain tumors to deliver a therapeutic dose of radiation with relative specificity for the tumor cells. Radiolabeled monoclonal antibodies may be a significant new therapeutic modality for these disease entities. These are the first studies in the United States to test such compartmental therapy of leptomeningeal neoplasms and brain tumor resection cavities with radiolabeled monoclonal antibodies.

该协议包含两个活动组件，每个组件分配一个单独的 杜克IRB号，和第三个组成部分，这已经成功地 已完成，现已关闭。 已完成的组件 利用~（131）I标记的~（81）C_6单克隆抗体治疗 肿瘤转移至软脑膜的患者。 的目的 这项研究是为了确定安全性和最大耐受剂量 鞘内注射131 I标记的81 C6单克隆抗体治疗 转移到软脑膜的肿瘤。 其中一部分 方法，使用与131 I缀合的81 C6 IgG单克隆抗体 治疗转移到软脑膜的肿瘤，或 与脑脊液相通的术后肿瘤囊腔 液 这是一项I期剂量递增研究，旨在确定 毒性特征和最大耐受同位素剂量。 协议开始了 在40 mCi的131 I下并以20 mCi的增量递增（即，六十八十一百 等mCi），每个剂量水平3-6名患者的队列中，直至达到最大剂量 达到耐受剂量。 对缓解进行了二次评估。 的 单次鞘内注射131 I-81 C6的最大耐受剂量 在成人患者中的给药剂量为80 mCi 131 I-81 C6（10 mg蛋白质）。 剂量限制性毒性为血液学毒性。 我们治疗了31名 在13例患者中观察到1例部分缓解和疾病稳定 31例（42%）。 该协议的这一部分已成功地 已完成，并发表了描述结果的手稿 (see附副本）。 该协议的一个活动组件利用 ~（131）I标记的~（81）C_6单克隆抗体治疗原发性肝癌的临床研究 原发性或转移性恶性脑肿瘤， 囊腔切除术 本研究的目的是确定 ~（131）I标记~（81）C_6单克隆抗体安全性和最大耐受剂量 将抗体施用到手术产生的囊性肿瘤切除术中 原发性或转移性恶性脑肿瘤患者的空洞。 第二种活性成分利用131 I标记的81 C6单克隆抗体， 抗体在 复发性囊性胶质瘤患者的治疗。 本研究的目的是确定 给予的131 I标记的81 C6单克隆抗体的耐受剂量 复发性肿瘤患者的自然发生的肿瘤囊肿腔 囊性神经胶质瘤 与131 I偶联的81 C6 IgG单克隆抗体是 用于治疗复发性囊性胶质瘤患者，或 原发性或转移性恶性脑肿瘤患者， 手术造成的囊性切除空洞。 这些是第一阶段剂量- 旨在确定毒性特征的递增研究， 上述每个患者群体的最大耐受同位素剂量。 的 方案开始于20 mCi 131 I，并以20 mCi增量递增 （即40、60、80、100等mCi），每剂量3-6例患者的队列 直至达到最大耐受剂量。 响应 二次评价。 这些研究正在继续增加患者。 我们已确定最大耐受剂量为100 mCi ~（131）I-81 C6（20 mg蛋白质）， 囊腔切除术 协议的这一分支已关闭， 手稿正在准备中。 活动方案的其他分支 各组成部分仍然可以应计。 这些疾病实体都是 癌症的毁灭性的、不可治愈的神经系统并发症（如存在） 治疗不够。 单克隆抗体的发展 为更特异性的肿瘤治疗提供了可能性， 与单克隆抗体或抗体片段反应。 抗体 它们对肿瘤细胞有特异性， 脑或脊髓可以与治疗性放射性同位素结合， 例如131 I。 然后可以将该缀合物鞘内递送， 软脑膜肿瘤，进入自然发生的肿瘤囊腔 用于囊性脑肿瘤，或插入外科手术产生的切除空腔 对于实体脑肿瘤来说， 肿瘤细胞的相对特异性。 放射性标记单克隆 抗体可能是一种重要的新的治疗方式， 疾病实体。 这是美国的第一项研究， 测试软脑膜肿瘤和脑的这种隔室疗法 肿瘤切除腔与放射性标记的单克隆抗体。