Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
The University of Chicago, Chicago, Illinois.
Clin Cancer Res. 2022 Feb 15;28(4):677-688. doi: 10.1158/1078-0432.CCR-21-1963.
This phase I study assessed the safety, pharmacokinetics (PKs), and efficacy of MIW815 (ADU-S100), a novel synthetic cyclic dinucleotide that activates the stimulator of IFN genes (STING) pathway, in patients with advanced/metastatic cancers.
Patients (n = 47) received weekly i.t. injections of MIW815, 50 to 6,400 μg, on a 3-weeks-on/1-week-off schedule.
A maximum tolerated dose was not reached. Most common treatment-related adverse events were pyrexia (17%), chills, and injection-site pain (each 15%). MIW815 was rapidly absorbed from the injection site with dose-proportional PK, a rapid terminal plasma half-life (approximately 24 minutes), and high interindividual variability. One patient had a partial response (PR; Merkel cell carcinoma); two patients had unconfirmed PR (parotid cancer, myxofibrosarcoma). Lesion size was stable or decreased in 94% of evaluable, injected lesions. RNA expression and immune infiltration assessments in paired tumor biopsies did not reveal significant on-treatment changes. However, increases in inflammatory cytokines and peripheral blood T-cell clonal expansion suggested systemic immune activation.
MIW815 was well tolerated in patients with advanced/metastatic cancers. Clinical activity of single-agent MIW815 was limited in this first-in-human study; however, evidence of systemic immune activation was seen.
本 I 期研究评估了新型合成环状二核苷酸 MIW815（ADU-S100）在晚期/转移性癌症患者中的安全性、药代动力学（PK）和疗效，MIW815 可激活干扰素基因刺激物（STING）通路。
患者（n=47）接受每周一次的 MIW815 腹腔内注射，剂量为 50 至 6400μg，每 3 周注射一次，1 周停药。
未达到最大耐受剂量。最常见的与治疗相关的不良事件是发热（17%）、寒战和注射部位疼痛（各 15%）。MIW815 从注射部位迅速吸收，具有剂量比例的 PK、快速的终末血浆半衰期（约 24 分钟）和高个体间变异性。1 例患者出现部分缓解（PR； Merkel 细胞癌），2 例患者出现未确认的 PR（腮腺癌、黏液纤维肉瘤）。94%的可评估注射病灶的病灶大小稳定或缩小。配对肿瘤活检的 RNA 表达和免疫浸润评估未显示出显著的治疗后变化。然而，炎症细胞因子的增加和外周血 T 细胞克隆扩增提示全身免疫激活。
MIW815 在晚期/转移性癌症患者中具有良好的耐受性。在这项首次人体研究中，单药 MIW815 的临床活性有限；然而，观察到了全身免疫激活的证据。
