Medical Oncology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
UCLouvain, Brussels, Belgium.
J Immunother Cancer. 2020 Oct;8(2). doi: 10.1136/jitc-2020-001153.
This phase Ib study evaluated the safety, clinical activity, pharmacokinetics, and pharmacodynamics (PD) of emactuzumab (anti-colony stimulating factor 1 receptor monoclonal antibody (mAb)) in combination with selicrelumab (agonistic cluster of differentiation 40 mAb) in patients with advanced solid tumors.
Both emactuzumab and selicrelumab were administered intravenously every 3 weeks and doses were concomitantly escalated (emactuzumab: 500 to 1000 mg flat; selicrelumab: 2 to 16 mg flat). Dose escalation was conducted using the product of independent beta probabilities dose-escalation design. PD analyzes were performed on peripheral blood samples and tumor/skin biopsies at baseline and on treatment. Clinical activity was evaluated using investigator-based and Response Evaluation Criteria In Solid Tumors V.1.1-based tumor assessments.
Three dose-limiting toxicities (all infusion-related reactions (IRRs)) were observed at 8, 12 and 16 mg of selicrelumab together with 1000 mg of emactuzumab. The maximum tolerated dose was not reached at the predefined top doses of emactuzumab (1000 mg) and selicrelumab (16 mg). The most common adverse events were IRRs (75.7%), fatigue (54.1%), facial edema (37.8%), and increase in aspartate aminotransferase and creatinine phosphokinase (35.1% both). PD analyzes demonstrated an increase of Ki67-activated CD8 T cells accompanied by a decrease of B cells and the reduction of CD14 CD16 monocytes in peripheral blood. The best objective clinical response was stable disease in 40.5% of patients.
Emactuzumab in combination with selicrelumab demonstrated a manageable safety profile and evidence of PD activity but did not translate into objective clinical responses.
NCT02760797.
这项 Ib 期研究评估了 emactuzumab（抗集落刺激因子 1 受体单克隆抗体（mAb））与 selicrelumab（激动性分化群 40 mAb）联合用于晚期实体瘤患者的安全性、临床活性、药代动力学和药效学（PD）。
emactuzumab 和 selicrelumab 均每 3 周静脉给药，剂量同时递增（emactuzumab：500 至 1000mg 平剂量；selicrelumab：2 至 16mg 平剂量）。剂量递增采用独立β概率剂量递增设计的乘积进行。PD 分析在基线和治疗时进行外周血样本和肿瘤/皮肤活检。临床活性采用基于研究者和基于实体瘤反应评价标准 1.1 的肿瘤评估进行评价。
在 selicrelumab 联合 emactuzumab 1000mg 时的 8、12 和 16mg 观察到 3 例剂量限制性毒性（均为输注相关反应（IRR））。在 emactuzumab（1000mg）和 selicrelumab（16mg）的预设最高剂量未达到最大耐受剂量。最常见的不良反应是 IRR（75.7%）、乏力（54.1%）、面部水肿（37.8%）和天冬氨酸氨基转移酶和肌酸磷酸激酶升高（均 35.1%）。PD 分析表明，外周血中 Ki67 激活的 CD8 T 细胞增加，B 细胞减少，CD14 CD16 单核细胞减少。患者的最佳客观临床反应是疾病稳定 40.5%。
emactuzumab 联合 selicrelumab 具有可管理的安全性特征和 PD 活性证据，但并未转化为客观的临床反应。
NCT02760797。
