Advanced phase I/II studies of targeted gene delivery in vivo: intravenous Rexin-G for gemcitabine-resistant metastatic pancreatic cancer.
Advanced phase I/II studies of targeted gene delivery in vivo: intravenous Rexin-G for gemcitabine-resistant metastatic pancreatic cancer.
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DOI：
10.1038/mt.2009.228
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发表时间：
2010-02
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Rexin-G是一种非复制性的病理靶向逆转录病毒载体，携带杀细胞周期蛋白G1构建体，在吉西他滨耐药胰腺癌的I/II期研究中进行了测试。患者静脉注射Rexin-G，剂量从1 × 1011菌落形成单位（cfu）每周2-3次（剂量0-1）递增至2 × 1011 cfu每周3次（剂量2），持续4周。如果毒性小于或等于1级，则继续治疗。未观察到剂量限制性毒性（DLT），也未观察到载体DNA整合、可复制逆转录病毒（RCR）或载体中和抗体。在9例可评价患者中，3/3例患者在剂量0-1时病情稳定（SD）。在第2次给药时，1/6例患者出现部分缓解（PR），5/6例患者出现SD。中位无进展生存期（PFS）在剂量0-1时为3个月，在剂量2时>7.65个月。中位总生存期（OS）在剂量0-1时为4.3个月，在剂量2时为9.2个月。剂量0-1时的一年生存率为0%，而剂量2时为28.6%，表明OS与Rexin-G剂量之间存在剂量-反应关系。综上所述，这些数据表明（i）Rexin-G是安全的，耐受性良好，（ii）Rexin-G可能有助于控制肿瘤生长，并可能延长吉西他滨耐药胰腺癌的生存期，因此，获得美国食品和药物管理局（FDA）的快速通道指定为胰腺癌的二线治疗。
Rexin-G, a nonreplicative pathology-targeted retroviral vector bearing a cytocidal cyclin G1 construct, was tested in a phase I/II study for gemcitabine-resistant pancreatic cancer. The patients received escalating doses of Rexin-G intravenously from 1 × 1011 colony-forming units (cfu) 2–3× a week (dose 0–1) to 2 × 1011 cfu 3× a week (dose 2) for 4 weeks. Treatment was continued if there was less than or equal to grade 1 toxicity. No dose-limiting toxicity (DLT) was observed, and no vector DNA integration, replication-competent retrovirus (RCR), or vector-neutralizing antibodies were noted. In nine evaluable patients, 3/3 patients had stable disease (SD) at dose 0–1. At dose 2, 1/6 patients had a partial response (PR) and 5/6 patients had SD. Median progression-free survival (PFS) was 3 months at dose 0–1, and >7.65 months at dose 2. Median overall survival (OS) was 4.3 months at dose 0–1, and 9.2 months at dose 2. One-year survival was 0% at dose 0–1 compared to 28.6% at dose 2, suggesting a dose–response relationship between OS and Rexin-G dosage. Taken together, these data indicate that (i) Rexin-G is safe and well tolerated, and (ii) Rexin-G may help control tumor growth, and may possibly prolong survival in gemcitabine-resistant pancreatic cancer, thus, earning US Food and Drug Administration's (FDA) fast-track designation as second-line treatment for pancreatic cancer.
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