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

描述（由申请人提供）：高危神经母细胞瘤（NB）具有广泛的转移。目前的治疗处于毒性极限，治愈率低至不可接受的30%。GD 2是抗体治疗的既定靶标。有效的治疗性单克隆抗体（MoAb）可以利用GD 2结合动力学（慢koff）和有效的ADCC和CMC功能。在过去的20年里，小鼠抗GD 2单克隆抗体m3 F8被选择用于临床研究。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疗效和安全性。抗GD 2单克隆抗体治疗的主要限制是疼痛副作用，特别是对于小鼠单克隆抗体如m3 F8，它是免疫原性的障碍。 目的/假设：人源化形式的3F 8（hu 3F 8）可以潜在地克服这两个限制。提出hu 3F 8的I期剂量递增研究以探索给药方案的两端。在低剂量下，hu 3F 8的疼痛副作用可以大大降低;在高剂量下，抗肿瘤效果可以大大提高。主要目标是建立最小/无疼痛副作用的最大耐受剂量（MTD）和无剂量限制性毒性（DLT）的MTD。次要目标是研究hu 3F 8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：将测试hu 3F 8的六个剂量水平（0.06、0.15、0.3、0.6、1.5、3 mg/kg/剂量），以两次注射hu 3F 8的形式给予，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化阿片类药物补救治疗。疼痛的DLT定义为在两小时内需要七次或更多次（平均值+2SD）剂量的阿片类药物。高血压的DLT定义为需要抗高血压药物治疗>24小时。将比较每个剂量水平下所需的平均急救次数与MSKCC同期研究中使用的20 mg/m2 m3 F8的平均急救次数。本研究最多将治疗36例患者;如果没有DLT，则仅需要21例患者完成研究。将分析每次注射hu 3F 8后168小时内的血清PK。将使用INSS（NB）或RECIST标准（GD 2阳性实体瘤）监测抗肿瘤活性。 影响：该提议通过开发用于转移性复发性NB和GD 2阳性实体瘤的动力学和功能改善的人源化抗体，建立在当前抗GD 2 MoAb疗法的基础上。无痛或疼痛“轻”方案可以极大地扩展抗GD 2单克隆抗体用于治疗儿童和成人中其他GD 2阳性癌症的未来应用的可能性。 公共卫生相关性：高风险的神经母细胞瘤扩散到骨骼和骨髓，并且非常难以治疗;即使使用化疗和放疗等强效药物，治愈的机会也低得令人无法接受。针对神经母细胞瘤抗原GD 2的鼠单克隆抗体（MoAb）m3 F8已显示出临床益处。下一代抗GD 2单克隆抗体已被人源化，hu 3F 8即使在低剂量下也具有对数倍的抗肿瘤活性增强，具有更少的疼痛副作用的潜力。提出了hu 3F 8在神经母细胞瘤和GD 2阳性肿瘤患者中的I期研究。

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.