Phase I/II Study of Oncolytic Herpes Simplex Virus NV1020 in Patients with Extensively Pretreated Refractory Colorectal Cancer Metastatic to the Liver
Phase I/II Study of Oncolytic Herpes Simplex Virus NV1020 in Patients with Extensively Pretreated Refractory Colorectal Cancer Metastatic to the Liver
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DOI：
10.1089/hum.2010.020
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发表时间：
2010-09-01
影响因子：
4.2
通讯作者：
Tawfik, Hoda
中科院分区：
文献类型：
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作者：
Geevarghese, Sunil K.;Geller, David A.;Tawfik, Hoda
这项多中心I/II期研究评估了重复剂量NV1020（一种基因工程溶瘤性单纯疱疹病毒）在晚期转移性结直肠癌（mCRC）患者中的安全性、药代动力学和抗肿瘤作用。以肝脏为主的mCRC患者通过每周肝动脉输注接受4次固定剂量的NV1020，随后进行2个或更多周期的常规化疗。第一阶段包括接受3x10(6)、1x10(7)、3x10(7)和1x10(8)斑块形成单位(PFU)/剂量的队列，以确定第二阶段的最佳生物剂量（OBD）。基于RECIST（实体瘤反应评价标准）的盲独立计算机断层扫描评价评估肝脏肿瘤反应。I期和II期分别入组13例和19例患者。每次注射NV1020后，患者出现短暂的轻中度发热反应。3/4级病毒相关毒性仅限于两例患者的暂时性淋巴细胞减少。未检测到NV1020脱落。同时发生的细胞因子和1级凝血扰动的剂量限制为1 × 10(8) PFU/剂量，被认为是OBD。所有22例OBD患者此前均接受过5-氟尿嘧啶治疗；大多数患者接受奥沙利铂或伊立替康治疗（50%同时接受这两种治疗），许多患者至少接受一种靶向药物治疗。服用NV1020后，50%的患者病情稳定。化疗后肿瘤总控制率最佳为68%（部分缓解1例，病情稳定14例）；这与基线变量或化疗无关。中位进展时间为6.4个月（95%可信区间：2,8.9）；中位总生存期为11.8个月（95%可信区间：8.3,20.7）。一年生存率为47.2%。我们得出结论，NV1020在mCRC中稳定肝转移，毒性最小。它可能会使转移灶重新敏感，以挽救化疗并延长总生存期。一项随机II/III期试验现在看来是合理的。
This multicenter phase I/II study evaluated the safety, pharmacokinetics, and antitumor effects of repeated doses of NV1020, a genetically engineered oncolytic herpes simplex virus, in patients with advanced metastatic colorectal cancer (mCRC). Patients with liver-dominant mCRC received four fixed NV1020 doses via weekly hepatic artery infusion, followed by two or more cycles of conventional chemotherapy. Phase I included cohorts receiving 3x10(6), 1x10(7), 3x10(7), and 1x10(8) plaque-forming units (PFU)/dose to determine the optimal biological dose (OBD) for phase II. Blind independent computed tomography scan review was based on RECIST (response evaluation criteria in solid tumors) to assess hepatic tumor response. Phase I and II enrolled 13 and 19 patients, respectively. Patients experienced transient mild-moderate febrile reactions after each NV1020 infusion. Grade 3/4 virus-related toxicity was limited to transient lymphopenia in two patients. NV1020 shedding was not detected. Simultaneous cytokine and grade 1 coagulation perturbations were dose-limiting at 1x10(8) PFU/dose, considered the OBD. All 22 OBD patients had previously received 5-fluorouracil; most had received oxaliplatin or irinotecan (50% had both), many with at least one targeted agent. After NV1020 administration, 50% showed stable disease. The best overall tumor control rate after chemotherapy was 68% (1 partial response, 14 stable disease); this did not correlate with baseline variables or chemotherapy. Median time to progression was 6.4 months (95% confidence interval: 2, 8.9); median overall survival was 11.8 months (95% confidence interval: 8.3, 20.7). One-year survival was 47.2%. We conclude that NV1020 stabilizes liver metastases with minimal toxicity in mCRC. It may resensitize metastases to salvage chemotherapy and extend overall survival. A randomized phase II/III trial now appears justified.