Department of Medical Oncology, University of Colorado, Denver, Colorado, USA.
Clin Cancer Res. 2010 Feb 15;16(4):1256-63. doi: 10.1158/1078-0432.CCR-09-1267. Epub 2010 Feb 9.
PRO95780 is a fully human IgG1 monoclonal antibody that triggers the extrinsic apoptosis pathway through death receptor 5. This first-in-human study assessed the safety, tolerability, pharmacokinetics, and any early evidence of efficacy of PRO95780 in patients with advanced malignancies.
Target concentrations were predicted to occur at 10 mg/kg. Patients received up to eight cycles of PRO95780 i.v. using a 3+3 dose escalation design at 1 to 20 mg/kg every 14 days (every 28 days in cycle 1; stage 1), with cohort expansion at either the maximum tolerated dose or 10 mg/kg, whichever was lower (stage 2). Patients were evaluated for response every other cycle.
The maximum tolerated dose was not reached within this study. Four (8%) of 50 patients reported adverse events of greater than grade 2 at least possibly related to PRO95780, including 2 patients with reversible grade 3 transaminase elevation. The mean terminal half-life was 8.8 to 19.3 days, with dose-dependent increases in exposure (peak plasma concentration and area under the concentration) across 1 to 15 mg/kg. Most patients treated with 10 mg/kg or above achieved trough concentration above the target efficacious concentration at day 15 with moderate accumulation after multiple doses. No objective responses occurred, although three minor responses were observed in patients with colorectal and granulosa cell ovarian cancers (each treated with 4 mg/kg) and chondrosarcoma (10 mg/kg).
PRO95780 is safe and well tolerated at doses up to 20 mg/kg. Evidence of activity was noted in several different tumor types at 4 and 10 mg/kg. Pharmacokinetic analysis supports a dosing regimen of 10 to 15 mg/kg every 2 to 3 weeks.
PRO95780 是一种完全人源化 IgG1 单克隆抗体，通过死亡受体 5 触发外在凋亡途径。这项首次人体研究评估了 PRO95780 在晚期恶性肿瘤患者中的安全性、耐受性、药代动力学和任何早期疗效证据。
预计目标浓度在 10mg/kg 时出现。患者每 14 天静脉注射 PRO95780，采用 1 至 20mg/kg 的 3+3 剂量递增设计（第 1 周期每 28 天；第 1 阶段），最大耐受剂量或 10mg/kg 中的较低者（第 2 阶段）进行队列扩展。每隔一个周期评估患者的反应。
本研究未达到最大耐受剂量。50 名患者中有 4 名（8%）报告了至少可能与 PRO95780 相关的 2 级以上不良事件，其中 2 名患者出现可逆性 3 级转氨酶升高。平均终末半衰期为 8.8 至 19.3 天，1 至 15mg/kg 剂量范围内暴露量（峰值血浆浓度和浓度下面积）呈剂量依赖性增加。大多数接受 10mg/kg 或以上剂量治疗的患者在第 15 天达到了目标有效浓度以上的谷浓度，并且在多次给药后有中度蓄积。尽管在接受 4mg/kg 治疗的结直肠癌和颗粒细胞瘤卵巢癌患者和软骨肉瘤患者中观察到了 3 例轻微反应，但未发生客观反应。
PRO95780 在高达 20mg/kg 的剂量下安全且耐受良好。在 4 和 10mg/kg 时，在几种不同的肿瘤类型中观察到了活性证据。药代动力学分析支持每 2 至 3 周给予 10 至 15mg/kg 的给药方案。
