Phase 1b/2a Trial of the Superoxide Dismutase Mimetic GC4419 to Reduce Chemoradiotherapy-Induced Oral Mucositis in Patients With Oral Cavity or Oropharyngeal Carcinoma.
Phase 1b/2a Trial of the Superoxide Dismutase Mimetic GC4419 to Reduce Chemoradiotherapy-Induced Oral Mucositis in Patients With Oral Cavity or Oropharyngeal Carcinoma.
复制标题
DOI：
10.1016/j.ijrobp.2017.10.019
复制
发表时间：
2018-02-01
期刊：
影响因子：
--
通讯作者：
Buatti JM
中科院分区：
文献类型：
--
作者：
Anderson CM;Sonis ST;Lee CM;Adkins D;Allen BG;Sun W;Agarwala SS;Venigalla ML;Chen Y;Zhen W;Mould DR;Holmlund JT;Brill JM;Buatti JM
口腔粘膜炎（OM）仍然是一个严重的问题； 70% 接受放化疗 (CRT) 治疗口腔癌或口咽癌 (OCC) 的患者会出现严重的 OM。 CRT 产生的超氧化物(O2•-) 在引发OM 中起着重要作用。临床前研究表明，超氧化物歧化酶模拟物 GC4419 将 (O2•-) 转化为 O2 和 H2O2 会阻止这一重要步骤。我们假设 GC4419 可以安全地与 CRT 一起给药并减少严重的 OM。在一项剂量和持续时间递增研究中，接受最终或术后调强 (IM) RT 加顺铂治疗的局部晚期 OCC 患者通过 60 分钟静脉输注接受 GC4419，在 IMRT 前 < 60 分钟内结束，中至周五持续 3-7 周。 IMRT 期间和之后每周评估 OM 两次。 46 名患者在 11 个单独的剂量和持续时间队列中接受 GC4419：5 个队列在 3 周内每天接受 15-112 mg 剂量，剂量递增（N=20）； 3 个队列在 4-6 周内每天接受 112 mg 的治疗持续时间递增（N=12），然后另外 3 个队列在 6-7 周内每天接受 30 或 90 mg 的治疗（N=14）。未达到最大耐受剂量。剂量限制性毒性（3 级胃肠炎和低钠血症呕吐）在两个单独的组中每组中均发生了 112 mg 剂量限制性毒性。输注期间的恶心/呕吐和面部感觉异常似乎与 GC4419 剂量相关。 14 名患者中，有 4 名 (29%) 接受 60 Gy 剂量治疗 6-7 周后出现严重 OM，中位持续时间仅为 2.5 天。 GC4419 与 CRT 联合治疗 OCC 的安全性是可以接受的。毒性包括恶心/呕吐和感觉异常。选择 30 和 90 mg/d 的剂量，持续 7 周进行进一步研究。在一项探索性分析中，严重的 OM 出现频率低于预期且持续时间较短。
Oral mucositis (OM) remains a critical problem; 70% of patients receiving chemoradiation (CRT) for oral cavity or oropharynx cancers (OCC) develop severe OM. Superoxide (O2•-) generated by CRT plays a significant role in initiating OM. Pre-clinical studies demonstrated that conversion of (O2•-) to O2 and H2O2 by the superoxide dismutase mimetic GC4419 interdicts this essential step. We hypothesized that GC4419 could safely be administered with CRT and reduce severe OM. Patients with locally-advanced OCC treated with definitive or post-operative intensity-modulated (IM)RT plus cisplatin received GC4419 by 60-minute IV infusion, ending <60 minutes before IMRT, M-F for 3–7 weeks, in a dose and duration escalation study. OM was assessed twice weekly during and weekly after IMRT. 46 patients received GC4419 in 11 separate dosing and duration cohorts: dose escalation occurred in 5 cohorts receiving 15–112 mg/day over 3 weeks (N=20); duration escalation in 3 cohorts receiving 112 mg/day over 4–6 weeks (N=12), then 3 additional cohorts receiving 30 or 90 mg/day over 6–7 weeks (N=14). A maximum tolerated dose was not reached. One dose-limiting toxicity (Grade 3 gastroenteritis and vomiting with hyponatremia) occurred in each of two separate cohorts @112 mg. Nausea/vomiting and facial paresthesia during infusion appeared to be GC4419 dose-related. Severe OM occurred through 60 Gy in 4 of 14 patients (29%) dosed for 6–7 weeks, with median duration of only 2.5 days. Safety of GC4419 concurrently with CRT for OCC was acceptable. Toxicities included nausea/vomiting and paresthesia. Doses of 30 and 90 mg/d administered for 7 weeks were selected for further study. In an exploratory analysis, severe OM appeared less frequent and briefer than expected.
登录
查看更多内容
影响因子：
3.1
作者：
Barber, Claire;Powell, Roy;Hewett, Julie
通讯作者：
Hewett, Julie
影响因子：
45.3
作者：
Henke, Michael;Alfonsi, Marc;Berger, Dietmar
通讯作者：
Berger, Dietmar
影响因子：
45.3
作者：
Leenstra, James L.;Miller, Robert C.;Loprinzi, Charles L.
通讯作者：
Loprinzi, Charles L.
影响因子：
6.2
作者：
Nonzee, Narissa J.;Dandade, Neal A.;Bennett, Charles L.
通讯作者：
Bennett, Charles L.
DOI：
10.1016/j.ijrobp.2007.01.053
发表时间：
2007-07-15
影响因子：
7
作者：
Elting, Linda S.;Cooksley, Catherine D.;Garden, Adam S.
通讯作者：
Garden, Adam S.