GWN323（抗 GITR）单药及联合 spartalizumab（抗 PD-1）治疗晚期实体瘤和淋巴瘤患者的 I/ Ib 期首次人体开放标签剂量递增研究。

First-in-human phase I/Ib open-label dose-escalation study of GWN323 (anti-GITR) as a single agent and in combination with spartalizumab (anti-PD-1) in patients with advanced solid tumors and lymphomas.

机构信息

Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Division of Oncology, Tel-Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.

出版信息

J Immunother Cancer. 2021 Aug;9(8). doi: 10.1136/jitc-2021-002863.

DOI:10.1136/jitc-2021-002863

PMID:34389618

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8365809/

Abstract

BACKGROUND

GWN323 is an IgG1 monoclonal antibody (mAb) against the glucocorticoid-induced tumor necrosis factor receptor-related protein. This first-in-human, open-label phase I/Ib study aimed to investigate the safety and tolerability and to identify the recommended doses of GWN323 with/without spartalizumab, an anti-programmed cell death receptor-1 agent, for future studies. Pharmacokinetics, preliminary efficacy and efficacy biomarkers were also assessed.

METHODS

Patients (aged ≥18 years) with advanced/metastatic solid tumors with Eastern Cooperative Oncology Group performance status of ≤2 were included. GWN323 (10-1500 mg) or GWN323+spartalizumab (GWN323 10-750 mg+spartalizumab 100-300 mg) were administered intravenously at various dose levels and schedules during the dose-escalation phase. Dose-limiting toxicities (DLTs) were assessed during the first 21 days in a single-agent arm and 42 days in a combination arm. Adverse events (AEs) were graded per National Cancer Institute-Common Toxicity Criteria for Adverse Events V.4.03 and efficacy was assessed using Response Evaluation Criteria in Solid Tumors V.1.1.

RESULTS

Overall, 92 patients (single-agent, n=39; combination, n=53) were included. The maximum administered doses (MADs) in the single-agent and combination arms were GWN323 1500 mg every 3 weeks (q3w) and GWN323 750 mg+spartalizumab 300 mg q3w, respectively. No DLTs were observed with single-agent treatment. Three DLTs (6%, all grade ≥3) were noted with combination treatment: blood creatine phosphokinase increase, respiratory failure and small intestinal obstruction. Serious AEs were reported in 30.8% and 34.0%, and drug-related AEs were reported in 82.1% and 77.4% of patients with single-agent and combination treatments, respectively. Disease was stable in 7 patients and progressed in 26 patients with single-agent treatment. In combination arm patients, 1 had complete response (endometrial cancer); 3, partial response (rectal cancer, adenocarcinoma of colon and melanoma); 14, stable disease; and 27, disease progression. GWN323 exhibited a pharmacokinetic profile typical of mAbs with a dose-dependent increase in the pharmacokinetic exposure. Inconsistent decreases in regulatory T cells and increases in CD8+ T cells were observed in the combination arm. Gene expression analyses showed no significant effect of GWN323 on interferon-γ or natural killer-cell signatures.

CONCLUSIONS

GWN323, as a single agent and in combination, was well tolerated in patients with relapsed/refractory solid tumors. The MAD was 1500 mg q3w for single-agent and GWN323 750 mg+spartalizumab 300 mg q3w for combination treatments. Minimal single-agent activity and modest clinical benefit were observed with the spartalizumab combination.

TRIAL REGISTRATION NUMBER

NCT02740270.

摘要

背景

GWN323 是一种针对糖皮质激素诱导的肿瘤坏死因子受体相关蛋白的 IgG1 单克隆抗体（mAb）。这项首次人体、开放性、I/ Ib 期研究旨在探索 GWN323 的安全性和耐受性，并确定 GWN323 联合/不联合 Spartalizumab（一种抗程序性细胞死亡受体-1 药物）的推荐剂量，以便进行进一步研究。还评估了药代动力学、初步疗效和疗效生物标志物。

方法

纳入年龄≥18 岁、ECOG 体能状态≤2 的晚期/转移性实体瘤患者。GWN323（10-1500mg）或 GWN323+Spartalizumab（GWN323 10-750mg+Spartalizumab 100-300mg）以不同剂量水平和方案静脉给药，在剂量递增阶段。单药组中在第 21 天，联合组中在第 42 天评估剂量限制性毒性（DLT）。按照国立癌症研究所不良事件通用毒性标准 4.03 对不良事件（AE）进行分级，采用实体瘤反应评估标准 1.1 版评估疗效。

结果

共纳入 92 例患者（单药组 39 例，联合组 53 例）。单药组和联合组的最大给药剂量（MAD）分别为 GWN323 1500mg，每 3 周（q3w）一次和 GWN323 750mg+Spartalizumab 300mg，q3w。单药治疗未观察到 DLT。联合治疗中观察到 3 例 DLT（6%，均为≥3 级）：肌酸磷酸激酶升高、呼吸衰竭和小肠梗阻。单药和联合治疗组分别有 30.8%和 34.0%的患者发生严重 AE，分别有 82.1%和 77.4%的患者发生药物相关 AE。单药治疗中 7 例患者疾病稳定，26 例患者疾病进展。联合组中，1 例患者完全缓解（子宫内膜癌）；3 例患者部分缓解（直肠癌、结肠癌腺癌和黑色素瘤）；14 例患者疾病稳定；27 例患者疾病进展。GWN323 表现出典型的 mAb 药代动力学特征，随着药物暴露量的增加而呈剂量依赖性增加。联合组中观察到调节性 T 细胞减少和 CD8+T 细胞增加不一致。基因表达分析显示 GWN323 对干扰素-γ或自然杀伤细胞特征无显著影响。

结论

GWN323 作为单药和联合用药在复发性/难治性实体瘤患者中具有良好的耐受性。单药治疗的 MAD 为 1500mg，q3w，联合治疗的 MAD 为 GWN323 750mg+Spartalizumab 300mg，q3w。与 Spartalizumab 联合应用时，单药治疗的活性最小，临床获益适度。