STUDY OF MAB 216 WITH CHEMOTHERAPY FOR THE TREATMENT OF PEDIATRIC PATIENTS

MAB 216 联合化疗治疗儿科患者的研究

• 批准号: 7375289
• 负责人: CLARE J TWIST
• 金额: $ 0.32万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7375289
• 关键词: STUDY; MAB; 216; CHEMOTHERAPY; TREATMENT

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Primary Aims: 1. Estimate the maximum tolerable dose (MTD) of monoclonal antibody 216 (mAb 216), administered in two doses one week apart, to children with relapsed or refractory acute lymphoblastic leukemia (ALL). 2. Determine the dose-limiting toxicities (DLT) of mAb 216 given on this schedule, as a single agent and in combination with Vincristine. 3. Characterize the pharmacokinetic behavior of mAb 216 in children with relapsed or refractory ALL. Secondary Aims: 1. Preliminarily define the anti-tumor activity of mAb 216 within the confines of a Phase I study. 2. Assess the biologic activity of mAb 216 in patients with relapsed or refractory ALL. Goals ALL is the most common malignancy of childhood. Approximately 80% of childhood ALL is of B-cell lineage, and although with current therapy nearly 80% of children with ALL will be cured, for the remaining group of patients the need for new and different treatment strategies continues to be a therapeutic challenge. Agents that demonstrate specificity for leukemic blasts, but which do not share a toxicity profile with chemotherapy drugs, would be particularly advantageous for designing new strategies of anti-leukemia therapy. Our research has found that malignant B cells obtained from ALL, non-Hodgkin's lymphoma (NHL) patient biopsies, B-cell lines and normal human B-cells are killed in vitro by a subset of monoclonal antibodies (mAbs) encoded by the VH4-34 gene (variable heavy region), and that cytotoxicity of VH4-34 encoded Abs are highly specific for B cells. Because human mAb 216 was the most cytotoxic of the tested mAbs, it has been used for further study. Importantly, flow cytometry analysis of normal bone marrow stained with labeled mAb 216 and labeled anti CD34 showed that 216 does not react with stem cells, so although the normal peripheral B cells would be killed in vivo by mAb 216 treatment, they will repopulate. Furthermore, in vitro studies have demonstrated mAb 216's cytotoxicity on pre-B cells from children diagnosed with ALL. In vitro cytotoxicity of mAb 216 in combination with single chemotherapeutic agents has also been tested. Cell lines which have been derived from ALL blasts of different genotype and phenotype, were incubated with mAb 216 alone or in combination with vincristine, daunomycin, or L-asparaginase. All of these chemotherapeutic agents increased the degree of cytoxicity seen with either single agent chemotherapy or mAb 216 alone. However, the combination of vincristine with mAb 216 was particularly striking, resulting in enhanced cytoxicity an order of magnitude greater than that seen with either vincristine or mAb 216 alone. Through the RAID program, the NCI and its contractors have performed in rabbits, pharmacokinetic (PK) and toxicity studies of mAb 216 alone and when given in combination with Vincristine. On histopathologic examination, no drug-related changes were noted. By itself, three days after administration, mAb 216 produced a dose-related decrease in platelet count, and mean WBC counts were decreased at a 20 mg/kg dosage, primarily due to neutropenia. Both platelet and WBC counts recovered by Day 8, and there were no significant changes in serum chemistry parameters. Based on the results of toxicology studies, RAID investigators concluded that sustained systemic toxicity is not expected at the planned clinical doses (100-400 mg/m2/dose) of mAb 216 when given in combination with Vincristine. While this is the first Phase I trial of mAb 216 in pediatric patients, another VH4-34 derived antibody, HA-1A, has been tested in children. In those studies, there were no adverse events reported that were felt to be "definitely" or "probably related" to HA-1A. While not definitive, these results suggest that mAb 216 may be well tolerated in pediatric patients. Given the high risk nature of the patient population who will be eligible for treatment on this Phase I study, it is the intent of this trial design to: 1) allow testing of mAb 216 as a single agent in patients with relapsed ALL; 2) to determine the PK of mAb 216 when administered as a single agent; 3) to determine the toxicity profile of this antibody as a single agent; and 4) to assess the in vivo cytotoxicity of this antibody. The preclinical cytotoxicity data strongly suggest that mAb 216 may demonstrate clinical efficacy when used alone. However, there is compelling evidence that mAb 216, when used in combination with chemotherapy agents, particularly Vincristine, mediates a synergistic degree of cytoxicity against B-progenitor leukemic blasts. The study design of this clinical trial will therefore provide important information about the clinical impact of mAb 216 when used alone as well as in combination with chemotherapeutic agents.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。主要目的：1.评估单抗216分两次间隔一周给药治疗复发或难治性急性淋巴细胞白血病(ALL)的最大耐受量。2.测定本附表所列单抗216与长春新碱合用的剂量限制毒性(DLT)。3.研究mAb216在复发或难治性ALL患儿中的药代动力学行为。次要目标：1.在一期研究范围内初步确定单抗216的抗肿瘤活性。2.检测复发或难治性ALL患者单抗216的生物学活性。目标ALL是儿时最常见的恶习。大约80%的儿童ALL是B细胞系，尽管通过目前的治疗，近80%的ALL儿童将被治愈，但对于其余的患者来说，对新的和不同的治疗策略的需求仍然是一个治疗挑战。对白血病原始细胞表现出特异性，但与化疗药物没有相同毒性特征的药物，将对设计抗白血病治疗的新策略特别有利。我们的研究发现，从ALL、非霍奇金淋巴瘤(NHL)患者活检组织、B细胞系和正常人B细胞中获得的恶性B细胞可被VH4-34基因编码的一组单抗(可变重区)体外杀伤，并且VH4-34编码的单抗对B细胞具有高度特异性。由于人mAb216是所测试的mAb中细胞毒性最强的，因此它被用于进一步的研究。重要的是，用标记的mAb216和标记的抗CD34染色的正常骨髓的流式细胞术分析表明，216不与干细胞反应，因此，尽管mAb216会在体内杀死正常的外周B细胞，但它们会重新繁殖。此外，体外研究表明，单抗216‘S对初诊急性淋巴细胞白血病患儿的前B细胞有细胞毒作用。此外，还检测了单抗216与单一化疗药物联合应用的体外细胞毒性。将来自不同基因和表型的所有原始细胞系与mAb216单独或与长春新碱、柔红霉素或L-天冬酰胺酶联合孵育。所有这些化疗药物都增加了单药化疗或单抗216的细胞毒性程度。然而，长春新碱与单抗216的结合特别引人注目，导致增强的细胞毒性比单独使用长春新碱或单抗216大一个数量级。通过RAID计划，NCI及其承包商已经在兔身上进行了单抗216单独以及与长春新碱联合使用时的药代动力学(PK)和毒性研究。组织病理学检查未见药物相关性改变。就其本身而言，在给药三天后，mAb216引起与剂量相关的血小板计数下降，平均白细胞计数在20 mg/kg剂量下下降，主要是由于中性粒细胞减少。第8天，血小板和白细胞计数均恢复正常，血清化学参数无明显变化。根据毒理学研究的结果，突袭调查人员得出结论，在计划的临床剂量(100-400 mg/m2/剂量)的mAb216与长春新碱联合使用时，预计不会出现持续的全身毒性。虽然这是单抗216在儿科患者中的第一阶段试验，但另一种VH4-34衍生抗体HA-1A已经在儿童中进行了测试。在这些研究中，没有报告的不良事件被认为与HA-1a“肯定”或“可能有关”。虽然不是决定性的，但这些结果表明，单抗216在儿科患者中可能具有良好的耐受性。鉴于有资格接受这项第一阶段研究治疗的患者群体的高风险性质，这项试验设计的目的是：1)允许对复发性ALL患者进行单抗216的测试；2)确定单抗216作为单剂使用时的PK；3)确定这种抗体作为单剂的毒性；以及4)评估这种抗体的体内细胞毒性。临床前的细胞毒性数据强烈表明，单抗216单独使用时可能显示出临床疗效。然而，有令人信服的证据表明，当mAb216与化疗药物，特别是长春新碱联合使用时，对B祖细胞白血病母细胞具有协同程度的细胞毒性。因此，这项临床试验的研究设计将提供有关单抗216单独使用以及与化疗药物联合使用时的临床影响的重要信息。