MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.
Clin Cancer Res. 2013 Jul 1;19(13):3659-70. doi: 10.1158/1078-0432.CCR-12-3349. Epub 2013 May 9.
To evaluate the safety and pharmacokinetics of siltuximab, an anti-interleukin-6 chimeric monoclonal antibody (mAb) in patients with B-cell non-Hodgkin lymphoma (NHL), multiple myeloma, or Castleman disease.
In an open-label, dose-finding, 7 cohort, phase I study, patients with NHL, multiple myeloma, or symptomatic Castleman disease received siltuximab 3, 6, 9, or 12 mg/kg weekly, every 2 weeks, or every 3 weeks. Response was assessed in all disease types. Clinical benefit response (CBR; composite of hemoglobin, fatigue, anorexia, fever/night sweats, weight, largest lymph node size) was also evaluated in Castleman disease.
Sixty-seven patients received a median of 16 siltuximab doses for a median of 8.5 (maximum 60.5) months; 29 were treated 1 year or longer. There was no dose-limiting toxicity, antibodies to siltuximab, or apparent dose-toxicity relationship. The most frequently reported possible drug-related adverse events were thrombocytopenia (25%), hypertriglyceridemia (19%), neutropenia (19%), leukopenia (18%), hypercholesterolemia (15%), and anemia (10%). None of these events led to dose delay/discontinuation except for neutropenia and thrombocytopenia (n = 1 each). No treatment-related deaths occurred. C-reactive protein (CRP) suppression was most pronounced at 12 mg/kg every 3 weeks. Mean terminal-phase half-life of siltuximab ranged 17.73 to 20.64 days. Thirty-two of 37 (86%) patients with Castleman disease improved in 1 or more CBR component; 12 of 36 evaluable Castleman disease patients had radiologic response [complete response (CR), n = 1; partial response (PR), n = 11], including 8 of 19 treated with 12 mg/kg; 2 of 14 (14%) evaluable NHL patients had PR; 2 of 13 (15%) patients with multiple myeloma had CR.
No dose-related or cumulative toxicity was apparent across all disease indications. A dose of 12 mg/kg every 3 weeks was recommended on the basis of the high response rates in Castleman disease and the sustained CRP suppression. Randomized studies are ongoing in Castleman disease and multiple myeloma.
评估抗白细胞介素-6 嵌合单克隆抗体（mAb） siltuximab 在 B 细胞非霍奇金淋巴瘤（NHL）、多发性骨髓瘤或 Castleman 病患者中的安全性和药代动力学。
在一项开放性、剂量递增、7 个队列、I 期研究中，NHL、多发性骨髓瘤或有症状的 Castleman 病患者接受 siltuximab 3、6、9 或 12 mg/kg，每周一次、每两周一次或每三周一次。所有疾病类型均评估应答。在 Castleman 病中还评估了临床获益反应（CBR；血红蛋白、疲劳、厌食、发热/盗汗、体重、最大淋巴结大小的综合指标）。
67 例患者接受了中位数为 16 次 siltuximab 治疗，中位数为 8.5（最长 60.5）个月；29 例患者治疗时间为 1 年或更长时间。无剂量限制毒性、抗 siltuximab 抗体或明显的剂量毒性关系。最常报告的可能与药物相关的不良事件是血小板减少症（25%）、高甘油三酯血症（19%）、中性粒细胞减少症（19%）、白细胞减少症（18%）、高胆固醇血症（15%）和贫血（10%）。除中性粒细胞减少症和血小板减少症（各 1 例）外，这些事件均未导致剂量延迟/停药。无治疗相关死亡。在每 3 周接受 12 mg/kg 治疗时，C 反应蛋白（CRP）抑制最为明显。siltuximab 的平均终末半衰期范围为 17.73 至 20.64 天。37 例 Castleman 病患者中有 32 例（86%）在 1 个或多个 CBR 指标上有所改善；36 例可评估的 Castleman 病患者中有 12 例（33%）有影像学反应[完全缓解（CR），n=1；部分缓解（PR），n=11]，其中 19 例接受 12 mg/kg 治疗的患者中有 8 例；20 例可评估的 NHL 患者中有 2 例（15%）有 PR；13 例多发性骨髓瘤患者中有 2 例（15%）有 CR。
在所有疾病适应证中，均未观察到与剂量相关或累积毒性。基于 Castleman 病的高缓解率和持续的 CRP 抑制，推荐使用 12 mg/kg 每 3 周的剂量。在 Castleman 病和多发性骨髓瘤中正在进行随机研究。
