Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, Houston, Texas, USA
Cancer Research Clinic, Carolina Biooncology Institute, Huntersville, North Carolina, USA.
J Immunother Cancer. 2022 Mar;10(3). doi: 10.1136/jitc-2021-004223.
This phase I multicenter study was designed to evaluate the safety, tolerability, efficacy, and translational effects on the tumor microenvironment of itacitinib (Janus-associated kinase 1 (JAK1) inhibitor) in combination with epacadostat (indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor).
Patients with advanced or metastatic solid tumors were enrolled and received itacitinib (100-400 mg once a day) plus epacadostat (50-300 mg two times per day; group A), or itacitinib (100-400 mg once a day) plus parsaclisib or parsaclisib monotherapy (0.3-10 mg once a day; group B).
A total of 142 patients were enrolled in the study. The maximum tolerated dose was not reached for either the combination of itacitinib plus epacadostat (n=47) or itacitinib plus parsaclisib (n=90). One dose-limiting toxicity of serious, grade 3 aseptic meningitis was reported in a patient receiving itacitinib 300 mg once a day plus parsaclisib 10 mg once a day, which resolved when the study drugs were withdrawn. The most common treatment-related adverse events among patients treated with itacitinib plus epacadostat included fatigue, nausea, pyrexia, and vomiting, and for patients treated with itacitinib plus parsaclisib were fatigue, pyrexia, and diarrhea. In the itacitinib plus epacadostat group, no patient had an objective response. Among patients receiving itacitinib 100 mg once a day plus parsaclisib 0.3 mg once a day, three achieved partial response for an objective response rate (95% CI) of 7.1% (1.50 to 19.48). Treatment with itacitinib plus epacadostat demonstrated some increase in tumor CD8 T cell infiltration and minor changes in six plasma proteins, whereas treatment with itacitinib plus high-dose parsaclisib resulted in downregulation of 20 plasma proteins mostly involved in immune cell function, with no observed change in intratumoral CD8 T cell infiltration.
Adverse events with JAK1 inhibition combined with either IDO1 or PI3Kδ inhibition were manageable, but the combinations demonstrated limited clinical activity or enhancement of immune activation in the tumor microenvironment.
NCT02559492.
这项 I 期多中心研究旨在评估 itacitinib（Janus 相关激酶 1（JAK1）抑制剂）联合 epacadostat（吲哚胺 2,3-双加氧酶 1（IDO1）抑制剂）或 parsaclisib（磷酸肌醇 3-激酶 δ（PI3Kδ）抑制剂）治疗晚期或转移性实体瘤患者的安全性、耐受性、疗效和对肿瘤微环境的转化作用。
入组的患者为晚期或转移性实体瘤患者，接受 itacitinib（每天 100-400mg，一次）联合 epacadostat（每天两次，每次 50-300mg；A 组）或 itacitinib（每天 100-400mg，一次）联合 parsaclisib 或 parsaclisib 单药治疗（每天一次，0.3-10mg；B 组）。
该研究共纳入 142 例患者。联合 itacitinib 加 epacadostat（n=47）或联合 itacitinib 加 parsaclisib（n=90）均未达到最大耐受剂量。接受 itacitinib 300mg 每日一次加 parsaclisib 10mg 每日一次治疗的 1 例患者发生严重、3 级无菌性脑膜炎的剂量限制性毒性，停药后缓解。接受 itacitinib 加 epacadostat 治疗的患者中最常见的治疗相关不良事件包括疲劳、恶心、发热和呕吐，而接受 itacitinib 加 parsaclisib 治疗的患者中最常见的不良事件是疲劳、发热和腹泻。在 itacitinib 加 epacadostat 组中，没有患者出现客观缓解。接受 itacitinib 每日 100mg 加 parsaclisib 每日 0.3mg 治疗的患者中有 3 例获得部分缓解，客观缓解率（95%CI）为 7.1%（1.50 至 19.48）。与 IDO1 或 PI3Kδ 抑制联合使用 JAK1 抑制剂治疗可增加肿瘤 CD8 T 细胞浸润，并导致 6 种血浆蛋白发生微小变化，而与高剂量 parsaclisib 联合使用则导致 20 种主要参与免疫细胞功能的血浆蛋白下调，肿瘤内 CD8 T 细胞浸润无明显变化。
JAK1 抑制联合 IDO1 或 PI3Kδ 抑制的不良反应可控制，但联合治疗显示出有限的临床活性或增强肿瘤微环境中的免疫激活。
NCT02559492。
