A PHASE ll TRIAL OF RITUXAN IN MULTIPLE SCLEROSIS

Rituxan 治疗多发性硬化症的 ll 期试验

• 批准号: 7025009
• 负责人: DOROTHY ANNE CROSS
• 金额: $ 8.81万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-03 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7025009
• 关键词: B lymphocyte; antineoplastics; cerebrospinal fluid; clinical research; clinical trial phase II; drug screening /evaluation; human subject; human therapy evaluation; immunoglobulins; immunopathology; immunosuppressive; immunotherapy; leukocyte count; leukocyte depletion therapy; magnetic resonance imaging; monoclonal antibody; multiple sclerosis; patient oriented research; pharmacokinetics; relapse /recurrence

DESCRIPTION (provided by applicant): Rituximab is a humanized monoclonal antibody (Ab) against CD20 on B cells that is FDA-approved for the therapy of non- Hodgkin's lymphoma. It depletes B cells and plasmablasts (early plasma cells that still express CD20) from the circulation. Our preliminary data in three patients indicates B cells and plasmablasts are depleted from the CSF by rituximab. This K24 mid-career application is based upon a Phase II trial of rituximab in relapsing MS. Rituximab will be given at the standard dose of 4 intravenous doses of 375mg/m2. This regimen eliminates circulating cells expressing CD20 (B cells, plasmablasts) completely for 6-12 months. Circumstantial evidence strongly suggests that B cells and/or Ab are involved in the pathogenesis of MS. However, all data thus far are associative. To determine whether B cells truly play a role will require a controlled trial of their elimination to determine if the course of MS will be altered. We are undertaking a Phase II trial of the safety and MRI efficacy of Rituxan in 30 patients with active, relapsing MS, despite taking beta-interferon (BIFN) or glatiramer acetate (GA). All patients entering are volunteers and are fully informed of the risks involved and the alternatives. Patients continue taking BIFN or GA. To receive study drug, subjects must have at least one gadolinium-enhancing lesion on any of three pre-treatment brain MRIs, and must have had at least one clinical relapse in the 18 months prior to enrollment, despite being on a standard therapy (BIFN or GA). Endpoints are safety, in terms of toxicity and the possibility of worsening of MS, and efficacy based on MRI activity. The primary efficacy endpoint will be reduction in number of gadolinium-enhancing lesions on 3 brain MRIs performed post-treatment in comparison to the 3 MRIs performed pre-treatment. B cell and plasma cell numbers and activation status, level of immunoglobulin in the spinal fluid and serum will be measured pre- and post-treatment. Ab levels to several myelin antigens (human MOG, MBP, dilapidated and whole myelin) and MBP in CSF will be assayed pre- and post-treatment. The study takes place in the General Clinical Research Center at WUSM. Genentech is providing drug free-of-charge and some funding. The National MS Society has reviewed and approved this trial, and is funding the bulk of this trial, including MRI's, but the NMSS does not pay salaries of tenured faculty. PI spends 10 hrs per week seeing private outpatients, 2-6 hrs/week seeing inpatients, plus an additional 3-6 hrs/wk on dictations, disability forms, and dealing with phone calls related to private patients. PI also serves 2 mon/yr, on "service" as Neurology Ward or Consulting Attending and performs clinical trials Sponsored by pharmaceutical companies (reimbursement is better than for private patient care) in order to cover her salary. PI is applying for the K24 award to perform this trial, and to mentor junior persons as part of this and other research projects. With the K24, PI will decrease time devoted to private outpatients by 50%, will eliminate taking on any new private patients, and will transfer the care of many of her > 1,000 private patients to Drs. Parks and Naismith, and PI will be able to focus 30% more time on investigator-initiated trials and mentoring junior colleagues.

描述（由申请人提供）：利妥昔单抗是一种针对 B 细胞上 CD20 的人源化单克隆抗体 (Ab)，经 FDA 批准用于治疗非霍奇金淋巴瘤。它会消耗循环中的 B 细胞和浆母细胞（仍表达 CD20 的早期浆细胞）。我们对三名患者的初步数据表明，利妥昔单抗可耗尽脑脊液中的 B 细胞和浆母细胞。该 K24 职业生涯中期应用基于利妥昔单抗治疗复发性多发性硬化症的 II 期试验。利妥昔单抗将以 4 次静脉注射的标准剂量 375mg/m2 给予。该方案可在 6-12 个月内完全消除表达 CD20 的循环细胞（B 细胞、浆母细胞）。间接证据强烈表明 B 细胞和/或 Ab 参与 MS 的发病机制。然而，迄今为止所有数据都是关联的。为了确定 B 细胞是否真正发挥作用，需要对其消除进行对照试验，以确定 MS 的病程是否会改变。我们正在对 30 名活动性、复发性多发性硬化症患者进行一项 II 期试验，研究 Rituxan 的安全性和 MRI 疗效，尽管他们服用了 β-干扰素 (BIFN) 或醋酸格拉替雷 (GA)。所有进入的患者都是志愿者，并充分了解所涉及的风险和替代方案。患者继续服用 BIFN 或 GA。要接受研究药物，受试者必须在三项治疗前脑部 MRI 中的任何一项上至少有一个钆增强病变，并且必须在入组前 18 个月内至少有一次临床复发，尽管正在接受标准治疗（BIFN）或遗传算法）。终点是安全性（毒性和 MS 恶化的可能性）以及基于 MRI 活动的疗效。主要疗效终点是与治疗前进行的 3 次 MRI 相比，治疗后进行的 3 次脑部 MRI 中钆增强病变的数量减少。将在治疗前和治疗后测量 B 细胞和浆细胞数量以及激活状态、脊髓液和血清中的免疫球蛋白水平。将在治疗前和治疗后测定脑脊液中几种髓磷脂抗原（人 MOG、MBP、破旧髓磷脂和全髓磷脂）的抗体水平和 MBP。该研究在 WUSM 综合临床研究中心进行。基因泰克免费提供药物并提供一些资金。国家多发性硬化症协会已经审查并批准了这项试验，并为这项试验的大部分提供资金，包括 MRI，但 NMSS 不支付终身教职人员的工资。 PI 每周花 10 小时看望私人门诊患者，每周花 2-6 小时看望住院患者，另外每周还花 3-6 小时听写、残疾表格以及处理与私人患者相关的电话。 PI 还每年服务 2 个月，作为神经病房或咨询主治的“服务”，并进行由制药公司赞助的临床试验（报销比私人患者护理更好），以支付她的工资。 PI 正在申请 K24 奖来执行这项试验，并指导初级人员作为本研究项目和其他研究项目的一部分。借助 K24，PI 将减少 50% 的私人门诊时间，无需再接收任何新的私人患者，并将超过 1,000 名私人患者的护理转移给医生。 Parks 和 Naismith 以及 PI 将能够将 30% 的时间多集中在研究者发起的试验和指导初级同事上。