Purpose: Combination therapies targeting immunologic checkpoints have shown promise in treating multiple tumor types. We report safety and tolerability of MEDI0562, a humanized IgG1K OX40 mAb, in combination with durvalumab (anti-PD-L1), or tremelimumab (anti-CTLA-4), in adult patients with previously treated advanced solid tumors. Patients and Methods: In this phase I, multicenter, open-label study, patients received escalating doses of MEDI0562 (2.25, 7.5, or 22.5 mg) every 2 weeks in combination with durvalumab (1,500 mg) or tremelimumab (75 or 225 mg) every 4 weeks, intravenously, until unacceptable toxicity or progressive disease. Tumor assessments were performed every 8 weeks. The primary objective was to evaluate safety and tolerability. Results: Among the 27 and 31 patients who received MEDI0562 + durvalumab or MEDI0562 + tremelimumab, 74.1% and 67.7% reported a treatment-related adverse event (AE), and 22.2% and 19.4% experienced a treatment-emergent AE that led to discontinuation, respectively. The MTD of MEDI0562 + durvalumab was 7.5 mg MEDI0562 + 1,500 mg durvalumab; the maximum administered dose of MEDI0562 + tremelimumab was 22.5 mg MEDI0562 + 225 mg tremelimumab. Three patients in the MEDI0562 + durvalumab arm had a partial response. The mean percentage of Ki67+CD4+ and Ki67+CD8+ memory T cells increased by >100% following the first dose of MEDI0562 + durvalumab or tremelimumab in all dose cohorts. A decrease in OX40+FOXP3 regulatory T cells was observed in a subset of patients with available paired biopsies. Conclusions: Following dose escalation, moderate toxicity was observed in both treatment arms, with no clear efficacy signals demonstrated.

中文翻译：

---

MEDI0562（一种 OX40 激动剂单克隆抗体）与 Durvalumab 或 Tremelimumab 联合治疗晚期实体瘤成人患者的安全性和耐受性

目的：针对免疫检查点的联合疗法已显示出治疗多种肿瘤类型的前景。我们报告了 MEDI0562（一种人源化 IgG1K OX40 mAb）与 durvalumab（抗 PD-L1）或 tremelimumab（抗 CTLA-4）联合用于既往治疗过的晚期实体瘤成年患者的安全性和耐受性。患者和方法：在这项 I 期、多中心、开放标签研究中，患者每两周接受递增剂量的 MEDI0562（2.25、7.5 或 22.5 mg）联合 durvalumab（1,500 mg）或 tremelimumab（75 或 225 mg）每 4 周静脉注射一次，直至出现不可接受的毒性或疾病进展。每 8 周进行一次肿瘤评估。主要目的是评估安全性和耐受性。结果：在接受 MEDI0562 + durvalumab 或 MEDI0562 + tremelimumab 的 27 例和 31 例患者中，有 74 例。1% 和 67.7% 的人报告了与治疗相关的不良事件 (AE)，22.2% 和 19.4% 的人分别经历了导致停药的治疗引起的 AE。MEDI0562 + durvalumab 的 MTD 为 7.5 mg MEDI0562 + 1,500 mg durvalumab；MEDI0562 + tremelimumab 的最大给药剂量为 22.5 mg MEDI0562 + 225 mg tremelimumab。MEDI0562 + durvalumab 组的三名患者出现部分缓解。在所有剂量组中首次给予MEDI0562+durvalumab或tremelimumab后，Ki67+CD4+和Ki67+CD8+记忆T细胞的平均百分比增加＞100％。在进行配对活检的一组患者中观察到 OX40+FOXP3 调节性 T 细胞减少。结论：剂量递增后，两个治疗组均观察到中度毒性，但没有显示明确的疗效信号。7% 的人报告了与治疗相关的不良事件 (AE)，22.2% 和 19.4% 的人分别经历了导致停药的治疗引起的 AE。MEDI0562 + durvalumab 的 MTD 为 7.5 mg MEDI0562 + 1,500 mg durvalumab；MEDI0562 + tremelimumab 的最大给药剂量为 22.5 mg MEDI0562 + 225 mg tremelimumab。MEDI0562 + durvalumab 组的三名患者出现部分缓解。在所有剂量组中首次给予MEDI0562+durvalumab或tremelimumab后，Ki67+CD4+和Ki67+CD8+记忆T细胞的平均百分比增加＞100％。在进行配对活检的一组患者中观察到 OX40+FOXP3 调节性 T 细胞减少。结论：剂量递增后，两个治疗组均观察到中度毒性，但没有显示明确的疗效信号。7% 的人报告了与治疗相关的不良事件 (AE)，22.2% 和 19.4% 的人分别经历了导致停药的治疗引起的 AE。MEDI0562 + durvalumab 的 MTD 为 7.5 mg MEDI0562 + 1,500 mg durvalumab；MEDI0562 + tremelimumab 的最大给药剂量为 22.5 mg MEDI0562 + 225 mg tremelimumab。MEDI0562 + durvalumab 组的三名患者出现部分缓解。在所有剂量组中首次给予MEDI0562+durvalumab或tremelimumab后，Ki67+CD4+和Ki67+CD8+记忆T细胞的平均百分比增加＞100％。在进行配对活检的一组患者中观察到 OX40+FOXP3 调节性 T 细胞减少。结论：剂量递增后，两个治疗组均观察到中度毒性，但没有显示明确的疗效信号。