Phase 1b, Multicenter, Single Blinded, Placebo-Controlled, Sequential Dose Escalation Study to Assess the Safety and Tolerability of Topically Applied AG013 in Subjects With Locally Advanced Head and Neck Cancer Receiving Induction Chemotherapy
Phase 1b, Multicenter, Single Blinded, Placebo-Controlled, Sequential Dose Escalation Study to Assess the Safety and Tolerability of Topically Applied AG013 in Subjects With Locally Advanced Head and Neck Cancer Receiving Induction Chemotherapy
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DOI：
10.1002/cncr.28365
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发表时间：
2013-12-15
期刊：
影响因子：
6.2
通讯作者：
Murphy, Barbara A.
中科院分区：
文献类型：
--
作者：
Limaye, Sewanti Atul;Haddad, Robert I.;Murphy, Barbara A.
背景：口腔黏膜炎是局部晚期头颈癌诱导化疗的一个重要毒性反应。在接受顺铂、5-氟尿嘧啶（联合或不联合多西他赛）诱导的LAHNC受试者中进行的一项Ib期研究中，评价了AG 013（一种含有分泌粘膜保护剂人三叶因子1（hTFF 1）的重组乳酸乳球菌的口腔冲洗剂）的安全性和耐受性。在诱导周期1期间随访的52名LAHNC受试者中，共有25名发生溃疡性口腔粘膜炎（溃疡性口腔粘膜炎;世界卫生组织分级>2），并在周期2中随机分配至AG 013：安慰剂（5：2比例）。评价了每日1次、3次或6次的给药方案（分别为2 x 10（11）、6 x 10（11）和1.2 x 10（12）菌落形成单位/天）。使用世界卫生组织标准，从第2周期第1天至第14天每天评价OM。同时进行药代动力学评价，在血液中未检测到TSAG 013细菌。在治疗组之间，唾液和口腔粘膜中的口腔活AG 013细菌和hTFF 1水平相当。最常见的不良事件是恶心、口腔疼痛、疲劳、腹泻和粘膜炎症。只有12%（25起不良事件中的3起），主要是恶心，归因于研究药物：AG 013或安慰剂。疗效分析显示，与安慰剂相比，AG 013-受试者中发生腹泻的天数百分比减少了35%。所有安慰剂组受试者均经历了2天的无症状发作，而29%的AG 013组受试者的无症状发作持续0或1天。AG 013的使用减少了计划外的办公室和急诊室就诊。两组在口腔和咽喉疼痛、阿片类药物使用或胃造口管放置方面无差异。结论SAG 013安全且耐受性良好。初步疗效数据支持进一步研究。Cancer 2013;119：4268-4276. (c)2013年美国癌症协会
BACKGROUND: Oral mucositis (OM) is a significant toxicity of induction chemotherapy for locally advanced head and neck cancer (LAHNC). The safety and tolerability of AG013, an oral rinse containing recombinant Lactococcus lactis secreting mucosal protectant human trefoil factor 1 (hTFF1), was evaluated in a phase 1b study in LAHNC subjects who received induction with cisplatin, 5-fluorouracil, with or without docetaxel. Preliminary efficacy data were also obtained.METHODSA total of 25 of 52 LAHNC subjects who were followed during induction cycle 1 developed ulcerative oral mucositis (UOM; World Health Organization grade>2) and were randomized to AG013:placebo (5:2 ratio) for cycle 2. Dosing schedules of 1, 3, or 6 times daily were evaluated (2 x 10(11), 6 x 10(11), and 1.2 x 10(12) colony forming units per day, respectively). OM was evaluated daily from cycle 2, day 1 through 14, using World Health Organization criteria. Pharmacokinetic assessment was also conducted.RESULTSAG013 bacteria were not detected in blood. Oral live AG013 bacterial and hTFF1 levels in saliva and oral mucosa were equivalent among treatment groups. The most frequently occurring adverse events were nausea, oral pain, fatigue, diarrhea, and mucosal inflammation. Only 12% (3 of 25 adverse events), mainly nausea, were attributed to the investigational medicinal product: AG013 or placebo. Efficacy analysis showed a 35% reduction in percentage of days with UOM in AG013-subjects versus placebo. All placebo subjects experienced2 days of UOM, whereas 29% of AG013 subjects had UOM for 0 or 1 day. AG013 use resulted in fewer unscheduled office and emergency room visits. No differences were noted in mouth and throat soreness, opioid use, or gastrostomy tube placement.CONCLUSIONSAG013 was safe and well tolerated. Preliminary efficacy data support further study. Cancer 2013;119:4268-4276. (c) 2013 American Cancer Society.