Laurie Scott A, Bell John C, Atkins Harold L, Roach Joanne, Bamat Michael K, O'Neil James D, Roberts M Scot, Groene William S, Lorence Robert M
Division of Medical Oncology and Centre for Cancer Therapeutics, Ottawa Hospital Regional Cancer Centre, University of Ottawa, Ottawa, Ontario, Canada.
Clin Cancer Res. 2006 Apr 15;12(8):2555-62. doi: 10.1158/1078-0432.CCR-05-2038.
In a previous phase 1 study, adverse events, especially flu-like symptoms, were observed mainly following the first i.v. bolus dose of PV701, an oncolytic Newcastle disease virus. Desensitization to adverse events of subsequent doses occurred, allowing a 10-fold increase in the maximum tolerated dose for these doses. Although one-step desensitization (a single desensitizing dose with higher subsequent doses) addressed the tolerability of high repeat doses, additional testing was required to further improve tolerability of the initial dose. This study tested the hypothesis that two-step desensitization, using two dose increments before high repeat doses, would be well tolerated.
Sixteen adults with incurable solid tumors were enrolled. Cycles consisted of six PV701 doses over 2 weeks followed by a 1-week rest. Doses 1 to 2 were 1 and 12 x 10(9) plaque-forming units (pfu)/m(2), respectively, whereas doses 3 to 6 were escalated by cohort from 24 to 120 x 10(9) pfu/m(2).
No dose-limiting toxicities were observed, permitting dose escalation through cohort 4 (1, 12, 120, 120, 120, 120 x 10(9) pfu/m(2)). Mild flu-like symptoms were common following the first infusion, diminished with repeated dosing, and were less pronounced than those seen previously. Tumor regression was observed in a patient with anal carcinoma who enrolled with stable disease following palliative radiotherapy. Four patients with clearly progressing cancer before enrollment had disease stabilization of >/=6 months.
This novel two-step desensitization improved patient tolerability compared with the previous regimen. Toxicities were predictable and manageable. PV701, the first oncolytic virus to enter phase 1 i.v. testing, continues to show single-agent activity, warranting planned phase 2 trials.
在先前的1期研究中，主要在首次静脉推注溶瘤新城疫病毒PV701后观察到不良事件，尤其是流感样症状。对后续剂量的不良事件出现了脱敏现象，使得这些剂量的最大耐受剂量增加了10倍。虽然一步脱敏（单次脱敏剂量后接更高的后续剂量）解决了高重复剂量的耐受性问题，但仍需要进一步测试以进一步提高初始剂量的耐受性。本研究检验了这样一个假设，即使用高重复剂量前的两个剂量递增步骤进行两步脱敏将具有良好的耐受性。
招募了16名患有无法治愈的实体瘤的成年人。周期包括在2周内给予6剂PV701，随后休息1周。第1至2剂分别为1和12×10⁹ 蚀斑形成单位（pfu）/m²，而第3至6剂按队列从24×10⁹ pfu/m²逐步递增至120×10⁹ pfu/m²。
未观察到剂量限制性毒性，允许剂量递增至第4队列（1、12、120、120、120、120×10⁹ pfu/m²）。首次输注后轻度流感样症状常见，随着重复给药而减轻，且比之前观察到的症状不那么明显。在一名肛门癌患者中观察到肿瘤消退，该患者在姑息性放疗后病情稳定时入组。4名入组前癌症明显进展的患者病情稳定≥6个月。
与先前的方案相比，这种新型的两步脱敏提高了患者的耐受性。毒性是可预测和可管理的。PV701是首个进入1期静脉注射测试的溶瘤病毒，继续显示出单药活性，值得开展计划中的2期试验。
