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

描述（由申请人提供）：高风险神经母细胞瘤（NB）具有广泛转移。目前的治疗已达到毒性极限，治愈率低至30%，令人无法接受。GD2是抗体治疗的既定靶点。有效的治疗性单克隆抗体（MoAb）可以利用GD2结合动力学（慢脱）和有效的ADCC和CMC功能。有了这些特点，在过去的20年里，我们选择了小鼠抗gd2 MoAb m3F8进行临床研究。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该方法的有效性和安全性。抗gd2 MoAb治疗的主要限制是疼痛副作用，特别是对于m3F8等小鼠MoAb，它是免疫原性的障碍。目的/假设：3F8的人源化形式（hu3F8）可以潜在地克服这两个限制。提出了hu3F8的I期剂量递增研究，以探索给药计划的两端。在低剂量的hu3F8下，疼痛副作用可以大大减少；高剂量时，其抗肿瘤作用明显增强。主要目标是确定最小/无疼痛副作用的最大耐受剂量（MTD），以及无剂量限制性毒性（DLT）的MTD。第二个目的是研究hu3F8的药代动力学（PK）。最后一个目标是评估抗肿瘤活性。研究设计：测试hu3F8的6个剂量水平（0.06、0.15、0.3、0.6、1.5、3mg /kg/剂），每次注射30分钟，间隔168小时。使用经典的3+3 I期设计，DLT将通过通用毒性标准（版本4.0，NCI）进行测量。疼痛副作用将采用标准的阿片类药物治疗。疼痛的DLT定义为两小时内需要7剂或更多（平均+ 2SD）剂量的阿片类药物。高血压的DLT定义为需要降压药物治疗bbbb24小时。每个剂量水平下所需的平均抢救次数将与MSKCC同期研究中使用的20mg /m2 m3F8进行比较。本研究最多将治疗36例患者；如果没有dlt，只需要21名患者就可以完成研究。分析每次注射hu3F8后168小时的血清PK。抗肿瘤活性将使用INSS监测NB，或使用RECIST标准监测gd2阳性实体瘤。影响：该建议建立在当前抗gd2 MoAb疗法的基础上，利用动力学和功能改进的人源化抗体治疗转移性复发NB和gd2阳性实体瘤。无痛或“终生”治疗方案可以极大地扩展抗gd2 MoAb在儿童和成人中治疗其他gd2阳性癌症的未来应用的可能性。

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. PUBLIC HEALTH RELEVANCE: High risk neuroblastoma spreads to bone and bone marrow, and is very difficult to treat; even with strong medicines like chemotherapy and radiation, the chance of cure is unacceptably low. Murine monoclonal antibody (MoAb) m3F8 targeted against the antigen GD2 on neuroblastoma has shown clinical benefits. Next generational anti-GD2 MoAb has been humanized, and hu3F8 has log-fold enhancement in anti-tumor activity even at low doses, with potential for less pain side effects. A phase I study of hu3F8 in patients with neuroblastoma and GD2-positive tumors is proposed.