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BACKGROUND

MEDI5395 is a recombinant attenuated Newcastle disease virus engineered to express a human granulocyte-macrophage colony-stimulating factor transgene. Preclinically, MEDI5395 demonstrated broad oncolytic activity, augmented by concomitant programmed cell death-1/programmed cell death ligand-1 (PD-L1) axis blockade. Durvalumab is an anti-PD-L1 immune checkpoint inhibitor approved for the treatment of various solid tumors. We describe the results of the first-in-human study combining intravenous MEDI5395 with durvalumab in patients with advanced solid tumors.

METHODS

This phase I, open-label, multicenter, dose-escalation, dose-expansion study recruited adult patients with advanced solid tumors, who had relapsed or were refractory or intolerant to ≥1 prior line of standard treatment. MEDI5395 was administered intravenously as six doses over 15-18 days. The dose-escalation phase assessed four-dose levels (10, 10, 10, 10 focus forming units (FFU)) of MEDI5395, with sequential or delayed durvalumab. Durvalumab 1500 mg was administered intravenously every 4 weeks up to 2 years. The dose-expansion phase was not initiated. The primary objectives were to evaluate safety and tolerability, dose-limiting toxicities (DLTs) and the dose and schedule of MEDI5395 plus durvalumab administration. Secondary objectives included the assessment of the efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of MEDI5395.

RESULTS

39 patients were treated with MEDI5395; 36 patients also received durvalumab. All 39 patients experienced ≥1 treatment-emergent adverse event (TEAE), most commonly fatigue (61.5%), nausea (53.8%) and chills (51.3%). Grade 3-4 TEAEs occurred in 27 (69.2%) patients; these were deemed MEDI5395-related in 12 (30.8%) patients. Two patients experienced a DLT, and the maximum tolerated dose of MEDI5395 with sequential and delayed durvalumab at study termination was 10 and 10 FFU, respectively. Four patients (10.3%) achieved a partial response (PR). Patients with PR or stable disease tended to have higher baseline PD-L1 and CD8+ levels in their tumor tissue. A tendency to dose-dependent pharmacokinetics of the viral genome was observed in whole blood and a tendency to dose-dependent viral shedding was observed in saliva and urine. Neutralizing antibodies were observed in all patients but did not appear to impact efficacy negatively.

CONCLUSION

This study demonstrates the feasibility, safety and preliminary efficacy of MEDI5395 with durvalumab in patients with advanced solid tumors.

TRIAL REGISTRATION NUMBER

NCT03889275.

背景

MEDI5395 是一种重组减毒新城疫病毒，经过工程改造后可表达人粒细胞-巨噬细胞集落刺激因子转基因。临床前研究表明，MEDI5395 具有广泛的溶瘤活性，并可增强同时使用的程序性细胞死亡-1/程序性细胞死亡配体-1（PD-L1）轴阻断的作用。度伐利尤单抗是一种抗 PD-L1 免疫检查点抑制剂，已被批准用于治疗各种实体瘤。我们描述了将 MEDI5395 与度伐利尤单抗联合用于治疗晚期实体瘤患者的首次人体研究结果。

方法

这是一项 I 期、开放标签、多中心、剂量递增和剂量扩展研究，招募了患有晚期实体瘤、既往复发或对至少 1 线标准治疗无效或不耐受的成年患者。MEDI5395 以 6 剂在 15-18 天内静脉给药。剂量递增阶段评估了 MEDI5395 的 4 个剂量水平（10、10、10、10 焦点形成单位（FFU）），同时序贯或延迟使用度伐利尤单抗。度伐利尤单抗 1500mg 每 4 周静脉给药，最长 2 年。剂量扩展阶段未启动。主要目的是评估安全性和耐受性、剂量限制性毒性（DLT）以及 MEDI5395 联合度伐利尤单抗的给药剂量和方案。次要目标包括评估 MEDI5395 的疗效、药代动力学、药效学和免疫原性。

结果

39 名患者接受了 MEDI5395 治疗；36 名患者还接受了度伐利尤单抗治疗。所有 39 名患者均发生了≥1 次治疗后出现的不良事件（TEAE），最常见的是疲劳（61.5%）、恶心（53.8%）和寒战（51.3%）。3 级或 4 级 TEAE 发生在 27 名（69.2%）患者中；其中 12 名（30.8%）患者认为与 MEDI5395 相关。有 2 名患者发生 DLT，研究结束时，MEDI5395 联合序贯和延迟使用度伐利尤单抗的最大耐受剂量分别为 10 和 10 FFU。4 名患者（10.3%）达到部分缓解（PR）。有 PR 或疾病稳定的患者倾向于在其肿瘤组织中具有更高的基线 PD-L1 和 CD8+水平。在全血中观察到病毒基因组的趋势性剂量依赖性药代动力学，在唾液和尿液中观察到病毒脱落的趋势性剂量依赖性。所有患者均观察到中和抗体，但似乎没有对疗效产生负面影响。