Combined radio- and immunotherapy of aggressive NHL

侵袭性 NHL 的放射和免疫联合治疗

• 批准号: 8661940
• 负责人: William A. Wegener
• 金额: $ 113.72万
• 依托单位: IMMUNOMEDICS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-21 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8661940
• 关键词: Antibodies; Antibody Formation; Antibody Therapy; Antigens; B-Cell Lymphomas; B-Lymphocytes; Biodistribution; Biological; CD22 gene; Cancer Center; Cell Count; Cells; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Combined Modality Therapy; Controlled Study; Data; Disease; Disease Resistance; Doctor of Philosophy; Dose; Drug Kinetics; Elderly; Ensure; Epratuzumab; Flow Cytometry; Fractionation; Goals; Health; High Dose Chemotherapy; Ibritumomab Tiuxetan; Image; Immunoglobulin G; Immunotherapeutic agent; Immunotherapy; Infusion procedures; Injection of therapeutic agent; Journals; Label; Lymphoma; MS4A1 gene; Malignant Neoplasms; Maximum Tolerated Dose; Medical; Monitor; Monoclonal Antibodies; Mus; Myron; New Agents; Non-Hodgkin' s Lymphoma; Patients; Peripheral; Phase; Phase II Clinical Trials; Positioning Attribute; Principal Investigator; Publications; Radiation; Radiation therapy; Radioconjugate; Radioimmunotherapy; Radionuclide Imaging; Refractory; Regimen; Relapse; Research Personnel; Residual Tumors; Resistance; Resort; Retreatment; Roswell Park Cancer Institute; Safety; Salvage Therapy; Scheme; Secondary to; Small Business Innovation Research Grant; Stem cell transplant; Therapeutic; Translating; Transplantation; Treatment Protocols; alternative treatment; arm; base; chemotherapy; design; experience; follow-up; improved; large cell Diffuse non-Hodgkin' s lymphoma; meetings; novel; oncology; pre-clinical; preclinical study; response; rituximab; standard care; treatment duration; treatment response; tumor; uptake

DESCRIPTION (provided by applicant): The main goal of this Phase I/II SBIR application is to translate rapidly preclinical findings that show the advantage of using a combination radioimmunotherapy plus immunotherapy treatment regimen that uses non-competing antibodies for the improved treatment of aggressive non-Hodgkin's lymphoma [NHL; i.e., diffuse large B-cell lymphoma (DLBCL) and mantle cell (MC)] patients prior to or in place of a high-dose chemotherapy/transplant. This treatment paradigm is intended to provide a meaningful treatment alternative for aggressive NHL Phase I/II clinical trials with 90Y-epratuzumab (humanized anti-CD22 IgG) and veltuzumab (humanized anti-CD20 IgG) have established the maximum tolerated dose (MTD) of a fractionated injection of 90Y-epratuzumab, and the optimal biological dose of veltuzumab, with both agents showing encouraging anti-tumor responses in follicular and aggressive NHL. This study first will re-evaluate the MTD for the fractionated weekly injection of 90Y-epratuzumab (previously found to be 2 x 20 mCi/m2) in a standard Phase I setting, and then proceed immediately into a Phase II trial to evaluate response and safety. The treatment regimen consists of 2 courses of veltuzumab spaced 4 weeks apart, with each course consisting of 4 weekly 120 mg/m2 of veltuzumab). 90Y-epratuzumab will be co-injected with the 3rd and 4th veltuzumab injection during the first veltuzumab course. This treatment regimen is based on preclinical data showing how a consolidation treatment with veltuzumab amplifies the treatment response of a radioconjugate treatment, but also how current anti-CD20-based radioimmunotherapy regimens may be reducing the impact of the therapeutic response by co-administered large amounts of competing anti-CD20 IgG. By substituting a 90Y-anti-CD22 radioconjugate, we can gain greater benefit from the radioconjugate and still provide the immunotherapeutic boost in response. Thus, this treatment scheme optimizes the use of both the radio- and immuno-conjugate for treating NHL. Standard pharmacokinetics and imaging studies will be performed in addition to safety and efficacy monitoring. 111In-epratuzumab imaging studies will be performed before the first veltuzumab treatment and with the first 90Y-epratuzumab injection to determine if there are any changes in biodistribution as a result of the prior veltuzumab injections. With encouraging results from this study, the company expects to initiate a registration trial. PUBLIC HEALTH RELEVANCE: This project will assess the safety and efficacy of a new combination radioimmunotherapy and immunotherapy treatment paradigm that will be applied to aggressive non-Hodgkin lymphoma. The treatment consists of a fractionated 90Y-DOTA-humanized anti-CD22 IgG (epratuzumab) given in combination with a humanized anti-CD20 IgG (veltuzumab), given in conjunction with the radioimmunotherapy, as well as a consolidation follow-up.

描述（由申请人提供）： 该I/II期SBIR应用的主要目标是快速转化临床前发现，其显示使用组合放射免疫疗法加免疫疗法治疗方案的优点，所述治疗方案使用非竞争性抗体用于改善侵袭性非霍奇金淋巴瘤[NHL;即，弥漫性大B细胞淋巴瘤（DLBCL）和套细胞（MC）]患者，在高剂量化疗/移植之前或代替高剂量化疗/移植。这种治疗范式旨在为90 Y-依帕珠单抗的侵袭性NHL I/II期临床试验提供有意义的治疗替代方案（人源化抗CD 22 IgG）和维妥珠单抗（人源化抗CD 20 IgG）已经建立了90 Y-依帕珠单抗的分次注射的最大耐受剂量（MTD）和维妥珠单抗的最佳生物剂量，两种药物在滤泡性和侵袭性NHL中均显示出令人鼓舞的抗肿瘤反应。本研究首先将在标准I期环境中重新评估90 Y-依帕珠单抗每周分次注射的MTD（先前发现为2 x 20 mCi/m2），然后立即进入II期试验，以评估反应和安全性。治疗方案由间隔4周的2个疗程的维妥珠单抗组成，每个疗程由每周4次120 mg/m2的维妥珠单抗组成。在第一个维妥珠单抗疗程期间，90 Y-依帕珠单抗将与第3次和第4次维妥珠单抗注射共同注射。该治疗方案基于临床前数据，这些数据显示了维妥珠单抗巩固治疗如何放大放射缀合物治疗的治疗应答，以及当前基于抗CD 20的放射免疫治疗方案如何通过共同施用大量竞争性抗CD 20 IgG来降低治疗应答的影响。通过取代90 Y-抗-CD 22放射性缀合物，我们可以从放射性缀合物中获得更大的益处，并且仍然提供免疫增强应答。因此，该治疗方案优化了放射性缀合物和免疫缀合物用于治疗NHL的用途。除安全性和疗效监测外，还将进行标准药代动力学和影像学研究。111 In-依帕珠单抗成像研究将在首次维妥珠单抗治疗前和首次90 Y-依帕珠单抗注射时进行，以确定是否存在由于先前维妥珠单抗注射导致的生物分布的任何变化。由于这项研究的结果令人鼓舞，该公司预计将启动注册试验。公共卫生相关性：该项目将评估一种新的联合放射免疫疗法和免疫疗法治疗范式的安全性和有效性，该治疗范式将应用于侵袭性非霍奇金淋巴瘤。治疗包括与放射免疫疗法联合给予的分级90 Y-DOTA-人源化抗CD 22 IgG（依帕珠单抗）与人源化抗CD 20 IgG（维妥珠单抗）联合给药，以及巩固随访。