Ozkaynak M F, Sondel P M, Krailo M D, Gan J, Javorsky B, Reisfeld R A, Matthay K K, Reaman G H, Seeger R C
Department of Pediatrics, Section of Hematology/Oncology, New York Medical College, Valhalla, NY, USA.
J Clin Oncol. 2000 Dec 15;18(24):4077-85. doi: 10.1200/JCO.2000.18.24.4077.
Ganglioside G(D2) is strongly expressed on the surface of human neuroblastoma cells. It has been shown that the chimeric human/murine anti-G(D2) monoclonal antibody (ch14.18) can induce lysis of neuroblastoma cells by antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. The purposes of the study were (1) to determine the maximum-tolerated dose (MTD) of ch14.18 in combination with standard dose granulocyte-macrophage colony-stimulating factor (GM-CSF) for patients with neuroblastoma who recently completed hematopoietic stem-cell transplantation (HSCT), and (2) to determine the toxicities of ch14.18 with GM-CSF in this setting.
Patients became eligible when the total absolute phagocyte count (APC) was greater than 1, 000/microL after HSCT. ch14.18 was infused intravenously over 5 hours daily for 4 consecutive days. Patients received GM-CSF 250 microg/m(2)/d starting at least 3 days before ch14.18 and continued for 3 days after the completion of ch14.18. The ch14.18 dose levels were 20, 30, 40, and 50 mg/m(2)/d. In the absence of progressive disease, patients were allowed to receive up to six 4-day courses of ch14.18 therapy with GM-CSF. Nineteen patients with neuroblastoma were treated.
A total of 79 courses were administered. No toxic deaths occurred. The main toxicities were severe neuropathic pain, fever, nausea/vomiting, urticaria, hypotension, mild to moderate capillary leak syndrome, and neurotoxicity. Three dose-limiting toxicities were observed among six patients at 50 mg/m(2)/d: intractable neuropathic pain, grade 3 recurrent urticaria, and grade 4 vomiting. Human antichimeric antibody developed in 28% of patients.
ch14.18 can be administered with GM-CSF after HSCT in patients with neuroblastoma with manageable toxicities. The MTD is 40 mg/m(2)/d for 4 days when given in this schedule with GM-CSF.
神经节苷脂G（D2）在人神经母细胞瘤细胞表面强烈表达。已表明，人/鼠嵌合抗G（D2）单克隆抗体（ch14.18）可通过抗体依赖性细胞毒性和补体依赖性细胞毒性诱导神经母细胞瘤细胞裂解。本研究的目的是：（1）确定ch14.18与标准剂量粒细胞-巨噬细胞集落刺激因子（GM-CSF）联合应用于近期完成造血干细胞移植（HSCT）的神经母细胞瘤患者的最大耐受剂量（MTD）；（2）确定在此情况下ch14.18与GM-CSF联合应用的毒性。
HSCT后总绝对吞噬细胞计数（APC）大于1000/μL的患者符合入选条件。ch14.18连续4天每天静脉输注5小时。患者在ch14.18前至少3天开始接受GM-CSF 250μg/m²/d，并在ch14.18完成后持续3天。ch14.18的剂量水平为20、30、40和50mg/m²/d。在无疾病进展的情况下，允许患者接受多达六个疗程、每个疗程4天的ch14.18与GM-CSF联合治疗。19例神经母细胞瘤患者接受了治疗。
共进行了79个疗程的治疗。未发生毒性死亡。主要毒性为严重神经性疼痛、发热、恶心/呕吐、荨麻疹、低血压、轻至中度毛细血管渗漏综合征和神经毒性。在6例接受50mg/m²/d治疗的患者中观察到3例剂量限制性毒性：顽固性神经性疼痛、3级复发性荨麻疹和4级呕吐。28%的患者产生了人抗嵌合抗体。
对于神经母细胞瘤患者，HSCT后可将ch14.18与GM-CSF联合应用，毒性可控。按照此方案与GM-CSF联合给药时，MTD为40mg/m²/d，连用4天。
