A phase 1 study of the CD40 agonist MEDI5083 in combination with durvalumab in patients with advanced solid tumors

<b>Aim:</b> This first-in-human study evaluated safety and efficacy of CD40 agonist MEDI5083 with durvalumab in patients with advanced solid tumors. <b>Methods:</b> Patients received MEDI5083 (3–7.5 mg subcutaneously every 2 weeks × 4 doses) and durvalumab (1500 mg every 4 weeks) either sequentially (N = 29) or concurrently (N = 9). Primary end point was safety; secondary end points included efficacy. <b>Results:</b> Thirty-eight patients received treatment. Most common adverse events (AEs) were injection-site reaction (ISR; sequential: 86%; concurrent: 100%), fatigue (41%; 33%), nausea (20.7%; 55.6%) and decreased appetite (24.1%; 33.3%). Nine patients had MEDI5083-related grade ≥3 AEs with ISR being the most common. Two patients experienced dose limiting toxicities (ISR). One death occurred due to a MEDI5083-related AE. MEDI5083 maximum tolerated dose was 5 mg. Objective response rate was 2.8% (1 partial response and 11 stable disease). <b>Conclusion:</b> MEDI5083 toxicity profile limits its further development. MEDI5083 is a molecule that was designed as a potential anticancer medication. Once inside the body, MEDI5083 connects to specific proteins found on the surface of immune cells and cancer cells. It can boost the immune system of the body in multiple ways to help kill cancer cells. In this clinical study, 38 patients with various types of cancers (bladder, breast, colon, head and neck, kidney, lung, and pancreas) were treated with MEDI5083 together with another anticancer medicine called durvalumab. MEDI5083 was given to patients as an injection under the skin once every 2 weeks. Durvalumab was given to patients as an infusion once every 4 weeks. The study monitored whether treatment caused unwanted side effects and whether MEDI5083 was able to shrink the size of tumors. A total of 34 of 38 patients who received treatment experienced unwanted reactions at the site of MEDI5083 treatment injection. These symptoms were long lasting and did not go away with an applied steroid treatment. A total of 5 of 38 patients experienced extreme tiredness and 4 of 38 patients experienced fever. Of 38 patients enrolled, 6 discontinued treatment because of a MEDI5083-related side effect. Only one patient had a decrease in the size of their cancer mass with treatment. Because of safety concerns, this study was not completed. The injectable form of MEDI5083 is not being further tested in patients with cancer. CD40 is widely expressed in multiple solid tumor types and activation of the CD40 pathway is an attractive approach to boost antitumor immune responses. MEDI5083 is a homodimeric fusion protein composed of a single chain fusion of three single-chain CD40L domains and an IgG4P domain fragment crystallizable linked by 9-glycine-serine linker regions, containing a mutated residue 194 (unpaired cysteine). MEDI5083 was designed to have better potency with prolonged exposure and less systemic toxicities. This multicenter, open-label, phase 1 study evaluated the safety and clinical activity of MEDI5083, administered sequentially or concurrently with durvalumab in adult patients with advanced solid tumors. Limited efficacy has been observed with the combination across cancer types evaluated. The most common MEDI5083-related adverse events were injection-site reaction, fatigue, and pyrexia. MEDI5083 demonstrated mobilization of B-cells and increased proliferating T-cell in peripheral blood. The toxicity profile of MEDI5083, when administered subcutaneously alone or in combination with durvalumab, did not support further development of this formulation.

**研究目的**：本项首次人体临床试验评估CD40激动剂MEDI5083联合德瓦鲁单抗（durvalumab）治疗晚期实体瘤患者的安全性与有效性。**研究方法**：受试者分为序贯给药组（N=29）与联合给药组（N=9），分别接受MEDI5083（每2周皮下注射3~7.5mg，共4剂）联合德瓦鲁单抗（每4周静脉输注1500mg）。本研究的主要终点为安全性，次要终点包括有效性。**研究结果**：共38例受试者接受治疗。最常见的不良事件（adverse events, AEs）为注射部位反应（injection-site reaction, ISR；序贯组：86%；联合组：100%）、疲劳（41%；33%）、恶心（20.7%；55.6%）及食欲下降（24.1%；33.3%）。9例受试者出现与MEDI5083相关的≥3级不良事件，其中以注射部位反应最为常见。2例受试者发生剂量限制性毒性（均为注射部位反应）。1例受试者因MEDI5083相关不良事件死亡。MEDI5083的最大耐受剂量为5mg。客观缓解率为2.8%（1例部分缓解，11例疾病稳定）。**研究结论**：MEDI5083的毒性特征限制了其进一步开发。MEDI5083是一款潜在抗癌候选分子，其设计原理为通过结合免疫细胞与癌细胞表面的特异性蛋白，多途径激活机体免疫系统以杀伤癌细胞。本临床研究共纳入38例罹患多种实体瘤（膀胱癌、乳腺癌、结肠癌、头颈部癌、肾癌、肺癌及胰腺癌）的患者，给予MEDI5083联合另一种抗癌药物德瓦鲁单抗治疗：MEDI5083采用每2周1次皮下注射给药，德瓦鲁单抗采用每4周1次静脉输注给药。本研究监测了治疗相关不良事件与MEDI5083的肿瘤缩小效果。共34/38例受试者出现MEDI5083注射部位不良反应，该症状持续时间较长，且外用类固醇治疗无法缓解。共5/38例受试者出现重度疲劳，4/38例出现发热。38例入组受试者中，6例因MEDI5083相关不良反应终止治疗。仅1例受试者经治疗后肿瘤体积缩小。鉴于安全性顾虑，本研究未完成全部计划。该皮下注射剂型的MEDI5083不再开展癌症患者相关后续临床试验。CD40在多种实体瘤中广泛表达，激活CD40通路是增强抗肿瘤免疫应答的极具潜力的策略。MEDI5083是一种同源二聚体融合蛋白，由3个单链CD40L结构域的单链融合片段、经9-甘氨酸-丝氨酸连接区连接的IgG4P结构域可结晶片段组成，携带194位突变残基（未配对半胱氨酸）。该药物设计旨在获得更持久的暴露量与更强的药效，同时降低全身毒性。本项多中心开放标签Ⅰ期临床试验评估了成人晚期实体瘤患者接受序贯或联合德瓦鲁单抗给药的MEDI5083的安全性与临床活性。在本次评估的多种癌种中，联合疗法的有效性有限。最常见的MEDI5083相关不良事件为注射部位反应、疲劳与发热。MEDI5083可动员外周血B细胞并增加增殖性T细胞比例。无论单独皮下给药还是联合德瓦鲁单抗给药，MEDI5083的毒性特征均不支持该剂型的进一步开发。