Phase I Study of Humanized 3F8 Monoclonal Antibody (Hu3F8) in Patients with High-

描述(申请人提供)：高危神经母细胞瘤(NB)具有广泛的转移。目前的治疗方法毒性有限，治愈率低到令人无法接受的30%。GD2是抗体治疗的既定靶点。有效的治疗性单抗(MOAB)可以利用GD2结合动力学(慢koff)和有效的ADCC和CMC功能。具有这些特性的小鼠抗GD2单抗m3F8在过去20年中被选作临床研究。骨髓组织学和MIBG扫描的NB反应以及延长的无进展生存期支持了这种方法的有效性和安全性。抗GD2单抗治疗的主要局限性是疼痛副作用，特别是对于像m3F8这样的小鼠单抗，它是免疫原性的障碍。目的/假设：人源化形式的3F8(Hu3F8)可能克服这两个限制。建议对hu3F8进行I期剂量递增研究，以探索给药计划的两端。小剂量hu3F8可显著降低疼痛副作用，大剂量hu3F8可显著提高抗肿瘤作用。主要目标是建立最大耐受量(MTD)和最大耐受量(MTD)，其中最大耐受量(MTD)具有最小/无疼痛副作用，MTD无剂量限制性毒性(DLT)。第二个目标是研究hu3F8的药代动力学。最后一个目标是评估抗肿瘤活性。研究设计：实验分为6个剂量水平(0.06，0.15，0.3，0.6，1.5，3 mg/kg/剂量)，每次注射两次，每次30分钟，相隔168小时。使用经典的3+3阶段I设计，DLT将根据通用毒性标准(版本4.0，NCI)进行测量。疼痛副作用将通过标准化的阿片类药物抢救进行治疗。疼痛的DLT被定义为需要在两小时内服用七剂或更多(平均+2SD)剂量的阿片类药物。高血压的DLT被定义为24小时内需要抗高血压药物。每个剂量水平所需的平均抢救次数将与MSKCC同期研究中使用的20毫克/平方米的m3F8的平均抢救次数进行比较。这项研究最多将治疗36名患者；如果没有DLTS，只需要21名患者就可以完成研究。分析每次注射hu3F8后168小时以上的血清PK。抗肿瘤活性将使用Nb的INSS或GD2阳性实体瘤的RECIST标准进行监测。影响：这项建议建立在目前的抗GD2单抗疗法的基础上，通过利用动力学和功能改进的人源化抗体来治疗转移性复发的NB和GD2阳性实体肿瘤。一种无痛或无痛的“Lite”疗法可以极大地扩大未来应用抗GD2单抗治疗儿童和成人其他GD2阳性癌症的可能性。

DESCRIPTION (provided by applicant): High risk neuroblastoma (NB) has widespread metastasis. Current therapy is at toxicity limit with an unacceptably low 30% cure rate. GD2 is an established target for antibody therapy. Effective therapeutic monoclonal antibodies (MoAb) can exploit GD2 binding kinetics (slow koff) and effective ADCC and CMC functions. Armed with these characteristics, mouse anti-GD2 MoAb m3F8 was chosen for clinical studies over the past 2 decades. NB response by marrow histology and MIBG scans, as well as prolonged progression-free survival support the efficacy and safety of this approach. The major limitation of anti-GD2 MoAb therapy is the pain side effect, and specifically for murine MoAb like m3F8, it is the hurdle of immunogenicity. Objective/Hypothesis: The humanized form of 3F8 (hu3F8) can potentially overcome both of these limitations. A phase I dose escalation study of hu3F8 is proposed to explore both ends of dosing schedule. At low dose hu3F8, pain side effects could be much reduced; at high dose hu3F8, anti-tumor effect could be much improved. The primary goal is to establish the maximum tolerated dose (MTD) with minimal/no pain side effects, and MTD with no dose-limiting toxicity (DLT). The secondary goal is to study the pharmacokinetics (PK) of hu3F8. The last goal is to assess anti-tumor activity. Study Design: Six dosage levels of hu3F8 will be tested (0.06, 0.15, 0.3, 0.6, 1.5, 3 mg/kg/dose), given as two injections of hu3F8 each over 30 minutes, 168 hours apart. Using a classic 3+3 phase I design, DLT will be measured by Common Toxicity Criteria (Version 4.0, NCI). Pain side effect will be treated with standardized opioid rescues. DLT of pain is defined as a need for seven or more (mean + 2SD) doses of opioids within two hours. DLT of hypertension is defined as a need for antihypertensive medication for >24 hours. The mean number of rescues required at each dose level will be compared to that for 20 mg/m2 of m3F8 used in concurrent studies at MSKCC. A maximum of 36 patients will be treated on this study; if there are no DLTs, only 21 patients will be needed to complete the study. Serum PK over 168 hours after each injection of hu3F8 will be analyzed. Anti- tumor activity will be monitored using INSS for NB, or RECIST criteria for GD2-positive solid tumors. Impact: This proposal builds on current anti-GD2 MoAb therapy by exploiting kinetically and functionally improved humanized antibodies for metastatic relapsed NB and GD2-positive solid tumors. A painless or pain-"lite" regimen can greatly expand the possibilities of future applications of anti-GD2 MoAb for treating other GD2-positive cancers in children and in adults.