Department of Medicine Division of Hematology and Oncology, University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, OH, USA.
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
Invest New Drugs. 2021 Aug;39(4):1057-1071. doi: 10.1007/s10637-021-01084-8. Epub 2021 Feb 23.
Background Tumor-associated macrophages (TAMs) promote tumor growth, metastasis, and therapeutic resistance via colony-stimulating factor-1 (CSF-1), acting through CSF-1 receptor (CSF-1R) signaling. This phase 1 study determined the safety, tolerability, pharmacokinetics-pharmacodynamics, immunogenicity, and efficacy of the anti-CSF-1R antibody LY3022855 in solid tumors. Methods Patients with advanced solid tumors refractory to standard therapy were enrolled and treated in 2 dosing cohorts: weight-based (part A) and non-weight-based (part B). Part A patients were assigned to intravenous (IV) dose-escalation cohorts: 2.5 mg/kg once per week (QW), 0.3 mg/kg QW, 0.6 mg/kg QW, 1.25 mg/kg once every 2 weeks (Q2W) and 1.25 mg/kg QW doses of LY3022855. Non-weight-based doses in part B were 100 mg and 150 mg IV QW. Results Fifty-two patients (mean age 58.6 ± 10.4 years) were treated with ≥1 dose of LY3022855 (range: 4-6). Five dose-limiting toxicities (left ventricular dysfunction, anemia, pancreatitis, rhabdomyolysis, and acute kidney injury) occurred in 4 patients. The non-weight-based 100 mg QW dose was established as the RP2D. The most common treatment-emergent adverse events were increase in liver function variables, fatigue, nausea, vomiting, diarrhea, anorexia, pyrexia, increased lipase, amylase, and lactate dehydrogenase. Clearance decreased with increasing dose and weight-based dosing had minimal effect on pharmacokinetics. Serum CSF-1, and IL-34 levels increased at higher doses and more frequent dosing, whereas TAMs and CD14dimCD16bright levels decreased. Three patients achieved stable disease. No responses were seen. Conclusions LY3022855 was well tolerated and showed dose-dependent pharmacokinetics-pharmacodynamics and limited clinical activity in a heterogenous solid tumor population. ClinicalTrials.gov ID NCT01346358 (Registration Date: May 3, 2011).
肿瘤相关巨噬细胞（TAMs）通过集落刺激因子-1（CSF-1）作用于 CSF-1 受体（CSF-1R）信号促进肿瘤生长、转移和治疗耐药性。这项 1 期研究旨在确定抗 CSF-1R 抗体 LY3022855 在实体瘤中的安全性、耐受性、药代动力学-药效学、免疫原性和疗效。
纳入了对标准治疗无反应的晚期实体瘤患者，并在 2 个剂量组中进行治疗：基于体重（第 A 部分）和非基于体重（第 B 部分）。第 A 部分患者被分配到静脉（IV）剂量递增队列：2.5mg/kg 每周一次（QW），0.3mg/kg QW，0.6mg/kg QW，1.25mg/kg 每 2 周一次（Q2W）和 1.25mg/kg QW 的 LY3022855 剂量。第 B 部分的非基于体重剂量为 100mg 和 150mg IV QW。
52 名患者（平均年龄 58.6±10.4 岁）接受了≥1 剂 LY3022855（范围：4-6）治疗。4 名患者出现 5 种剂量限制毒性（左心室功能障碍、贫血、胰腺炎、横纹肌溶解和急性肾损伤）。非基于体重的 100mg QW 剂量被确定为 RP2D。最常见的治疗后出现的不良反应是肝功能指标升高、疲劳、恶心、呕吐、腹泻、厌食、发热、脂肪酶、淀粉酶和乳酸脱氢酶升高。清除率随剂量增加而降低，基于体重的剂量对药代动力学的影响最小。较高剂量和更频繁的给药会导致血清 CSF-1 和 IL-34 水平升高，而 TAMs 和 CD14dimCD16bright 水平降低。3 名患者病情稳定。未观察到应答。
LY3022855 在异质性实体瘤人群中具有良好的耐受性，并表现出剂量依赖性的药代动力学-药效学和有限的临床活性。临床试验.gov 标识符 NCT01346358（注册日期：2011 年 5 月 3 日）。
