Phase I study of a recombinant attenuated oncolytic virus, MEDI5395 (NDV–GM-CSF), administered systemically in combination with durvalumab in patients with advanced solid tumors
Creators: name: Agrawal, Sonia
name: Dy, Grace K
name: Davar, Diwakar
name: Galanis, Evanthia
name: Harrington, Kevin J
name: Samson, Adel
name: Burton, Jenny
name: Patel, Sandip P
name: Fan, Chunling
name: Tu, Eric
name: Gong, Maozhen
name: Arnaldez, Fernanda
name: Laubscher, Kevin
name: Zamarin, Dmitriy
name: Durham, Nicholas
name: Borad, Mitesh J
name: Chen, Zhongying
name: Carneiro, Benedito A
name: Sheth, Siddharth
Publisher: name: BMJ
Year: 2024

description: <p>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 &ge;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<sup>8</sup>, 10<sup>9</sup>, 10<sup>10</sup>, 10<sup>11</sup> focus forming units (FFU)) of MEDI5395, with sequential or delayed durvalumab. Durvalumab 1500&thinsp;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 &ge;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<sup>11</sup> and 10<sup>10</sup> 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.</p>