Oncology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), UCM, CNIO, CIBERONC, Madrid, Spain.
VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain.
J Immunother Cancer. 2022 Mar;10(3). doi: 10.1136/jitc-2021-003255.
VCN-01 is an oncolytic adenovirus (Ad5 based) designed to replicate in cancer cells with dysfunctional RB1 pathway, express hyaluronidase to enhance virus intratumoral spread and facilitate chemotherapy and immune cells extravasation into the tumor. This phase I clinical trial was aimed to find the maximum tolerated dose/recommended phase II dose (RP2D) and dose-limiting toxicity (DLT) of the intravenous delivery of the replication-competent VCN-01 adenovirus in patients with advanced cancer.
Part I: patients with advanced refractory solid tumors received one single dose of VCN-01. Parts II and III: patients with pancreatic adenocarcinoma received VCN-01 (only in cycle 1) and nab-paclitaxel plus gemcitabine (VCN-concurrent on day 1 in Part II, and 7 days before chemotherapy in Part III). Patients were required to have anti-Ad5 neutralizing antibody (NAbs) titers lower than 1/350 dilution. Pharmacokinetic and pharmacodynamic analyses were performed.
26% of the patients initially screened were excluded based on high NAbs levels. Sixteen and 12 patients were enrolled in Part I and II, respectively: RP2D were 1×10 viral particles (vp)/patient (Part I), and 3.3×10 vp/patient (Part II). Fourteen patients were included in Part III: there were no DLTs and the RP2D was 1×10 vp/patient. Observed DLTs were grade 4 aspartate aminotransferase increase in one patient (Part I, 1×10 vp), grade 4 febrile neutropenia in one patient and grade 5 thrombocytopenia plus enterocolitis in another patient (Part II, 1×10 vp). In patients with pancreatic adenocarcinoma overall response rate were 50% (Part II) and 50% (Part III). VCN-01 viral genomes were detected in tumor tissue in five out of six biopsies (day 8). A second viral plasmatic peak and increased hyaluronidase serum levels suggested replication after intravenous injection in all patients. Increased levels of immune biomarkers (interferon-γ, soluble lymphocyte activation gene-3, interleukin (IL)-6, IL-10) were found after VCN-01 administration.
Treatment with VCN-01 is feasible and has an acceptable safety. Encouraging biological and clinical activity was observed when administered in combination with nab-paclitaxel plus gemcitabine to patients with pancreatic adenocarcinoma.
NCT02045602.
VCN-01 是一种溶瘤腺病毒（基于 Ad5），旨在在 RB1 通路功能失调的癌细胞中复制，表达透明质酸酶以增强病毒在肿瘤内的扩散，并促进化疗药物和免疫细胞渗透到肿瘤中。这项 I 期临床试验旨在确定静脉注射复制型 VCN-01 腺病毒在晚期癌症患者中的最大耐受剂量/推荐的 II 期剂量（RP2D）和剂量限制性毒性（DLT）。
第 I 部分：患有晚期难治性实体瘤的患者接受单次 VCN-01 剂量。第 II 部分和第 III 部分：患有胰腺腺癌的患者接受 VCN-01（仅在第 1 周期）和 nab-紫杉醇加吉西他滨（第 II 部分在第 1 天 VCN 同时给药，第 III 部分在化疗前 7 天）。患者需要具有低于 1/350 稀释度的抗 Ad5 中和抗体（NAb）滴度。进行了药代动力学和药效学分析。
根据高 NAb 水平，最初筛选的 26%的患者被排除在外。第 I 部分和第 II 部分分别纳入 16 名和 12 名患者：RP2D 分别为 1×10 病毒颗粒（vp）/患者（第 I 部分）和 3.3×10 vp/患者（第 II 部分）。第 III 部分纳入 14 名患者：无 DLT，RP2D 为 1×10 vp/患者。观察到的 DLT 为 1 名患者（第 I 部分，1×10 vp）的天门冬氨酸氨基转移酶 4 级升高，1 名患者的 4 级发热性中性粒细胞减少症和另 1 名患者的 5 级血小板减少症伴结肠炎（第 II 部分，1×10 vp）。在胰腺腺癌患者中，总缓解率为 50%（第 II 部分）和 50%（第 III 部分）。在六次活检中的五次中检测到肿瘤组织中的 VCN-01 病毒基因组（第 8 天）。所有患者均在静脉注射后检测到第二个病毒血浆峰和透明质酸酶血清水平升高，提示复制。在 VCN-01 给药后发现免疫生物标志物（干扰素-γ、可溶性淋巴细胞激活基因-3、白细胞介素（IL）-6、IL-10）水平升高。
VCN-01 的治疗是可行的，具有可接受的安全性。当与 nab-紫杉醇加吉西他滨联合用于胰腺腺癌患者时，观察到令人鼓舞的生物学和临床活性。
NCT02045602。
