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

人源化 3F8 单克隆抗体 (Hu3F8) 在高危人群中的 I 期研究

• 批准号: 8189124
• 负责人: NAI-KONG V CHEUNG
• 金额: $ 37.29万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8189124
• 关键词: Address; Adult; Adverse effects; Affinity; Antibody Therapy; Antigens; Antihypertensive Agents; Area; Aspirate substance; Benchmarking; Biopsy; Bone Marrow; Characteristics; Child; Children' s Oncology Group; Clinical; Clinical Research; Cohort Studies; Common Terminology Criteria for Adverse Events; Complement; Computer software; Data; Dose; Dose-Limiting; Drug Kinetics; FCGR3B gene; Future; GD2 Binding; Goals; Half-Life; Histological Techniques; Histology; Hour; Hypertension; Imaging Techniques; Immunotherapy; In Vitro; Injection of therapeutic agent; Kinetics; Magnetic Resonance Imaging; Malignant Neoplasms; Marrow; Maximum Tolerated Dose; Measures; Mediating; Medicine; Memorial Sloan-Kettering Cancer Center; Modeling; Monitor; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Neoplasm Metastasis; Neuroblastoma; Opioid; Outcome; Pain; Painless; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Positron-Emission Tomography; Progression-Free Survivals; Radiation; Regimen; Relapse; Research Design; Safety; Scanning; Schedule; Serum; Serum Markers; Solid Neoplasm; Testing; Therapeutic Monoclonal Antibodies; Time; Toxic effect; Translating; Urine; Xenograft procedure; antibody-dependent cell cytotoxicity; arm; base; bone; chemotherapy; cytotoxicity; density; design; dosage; high risk; humanized antibody; immunogenicity; improved; indexing; metaiodobenzylguanidine; monoclonal antibody 3F8; neutrophil; next generation; phase 1 study; programs; randomized trial; response; tumor

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.

描述（由申请人提供）：高风险神经母细胞瘤（NB）具有广泛的转移。目前的治疗已达到毒性极限，治愈率仅为 30%，低得令人无法接受。 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（慢速 koff）和有效的 ADCC 和 CMC 功能。凭借这些特性，在过去的 20 年里，小鼠抗 GD2 MoAb m3F8 被选用于临床研究。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有效性和安全性。抗 GD2 MoAb 疗法的主要限制是疼痛副作用，特别是对于 m3F8 等鼠类 MoAb，它是免疫原性的障碍。 目的/假设：3F8 (hu3F8) 的人源化形式有可能克服这两个限制。拟对 hu3F8 进行 I 期剂量递增研究，以探索给药方案的两端。低剂量的 hu3F8 可以大大减少疼痛副作用；高剂量的hu3F8，可以大大提高抗肿瘤效果。主要目标是确定具有最小/无疼痛副作用的最大耐受剂量 (MTD)，以及无剂量限制毒性 (DLT) 的 MTD。第二个目标是研究 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：将测试 hu3F8 的六种剂量水平（0.06、0.15、0.3、0.6、1.5、3 mg/kg/剂），两次注射 hu3F8，每次注射 30 分钟，间隔 168 小时。采用经典的 3+3 I 期设计，DLT 将通过通用毒性标准（4.0 版，NCI）进行测量。疼痛副作用将通过标准化阿片类药物救援来治疗。 DLT 疼痛定义为两小时内需要七次或更多（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超过 24 小时。每个剂量水平所需的平均救援次数将与 MSKCC 同期研究中使用的 20 mg/m2 m3F8 的救援次数进行比较。这项研究最多将治疗 36 名患者；如果没有 DLT，则只需 21 名患者即可完成研究。每次注射 hu3F8 后 168 小时内的血清 PK 将进行分析。将使用针对 NB 的 INSS 或针对 GD2 阳性实体瘤的 RECIST 标准来监测抗肿瘤活性。 影响：该提案建立在当前抗 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“轻度”治疗方案可以极大地扩展抗 GD2 MoAb 未来应用治疗儿童和成人其他 GD2 阳性癌症的可能性。 公共卫生相关性：高风险神经母细胞瘤会扩散到骨骼和骨髓，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 GD2 的鼠单克隆抗体 (MoAb) m3F8 已显示出临床益处。下一代抗 GD2 MoAb 已经人源化，hu3F8 即使在低剂量下，抗肿瘤活性也呈对数倍增强，并且可能减少疼痛副作用。拟对神经母细胞瘤和 GD2 阳性肿瘤患者进行 hu3F8 的 I 期研究。