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Abstract：
This trial assessed the efficacy of MR309 (a novel selective sigma-1 receptor ligand previously developed as E-52862) in ameliorating oxaliplatin-induced peripheral neuropathy (oxaipn). A discontinuous regimen of MR309 (400 mg/day, 5 days per cycle) was tested in patients with colorectal cancer receiving FOLFOX in a phase II, randomized, double-blind, placebo-controlled, multicenter clinical trial. Outcome measures included changes in 24-week quantitative measures of thermal sensitivity and total neuropathy score. In total, 124 patients were randomized (1:1) to MR309 or placebo. Sixty-three (50.8%) patients withdrew prematurely before completing 12 planned oxaliplatin cycles. Premature withdrawal because of cancer progression was less frequent in the MR309 group (7.4% vs 25.0% with placebo; p = 0.054). MR309 significantly reduced cold pain threshold temperature [mean treatment effect difference (SE) vs placebo: 5.29 (1.60)°C; p = 0.001] and suprathreshold cold stimulus-evoked pain intensity [mean treatment effect difference: 1.24 (0.57) points; p = 0.032]. Total neuropathy score, health-related quality-of-life measures, and nerve-conduction parameters changed similarly in both arms, whereas the proportion of patients with severe chronic neuropathy (National Cancer Institute Common Terminology Criteria for Adverse Events ≥ 3) was significantly lower in the MR309 group (3.0% vs 18.2% with placebo; p = 0.046). The total amount of oxaliplatin delivered was greater in the active arm (1618.9 mg vs 1453.8 mg with placebo; p = 0.049). Overall, 19.0% of patients experienced at least 1 treatment-related adverse event (25.8% and 11.9% with MR309 and placebo, respectively). Intermittent treatment with MR309 was associated with reduced acute oxaipn and higher oxaliplatin exposure, and showed a potential neuroprotective role for chronic cumulative oxaipn. Furthermore, MR309 showed an acceptable safety profile.
摘要：
该试验评估了MR309（一种新型选择性sigma-1受体配体，以前开发为E-52862）在改善奥沙利铂诱导的周围神经病变（oxaipn）中的功效。MR309的不连续方案(400毫克/天，每个周期5天）在II期接受FOLFOX的结直肠癌患者中进行了测试，随机化，双盲,安慰剂对照,多中心临床试验。结果测量包括热敏感性和总神经病变评分的24周定量测量的变化。总的来说,124例患者随机(1:1)接受MR309或安慰剂治疗。63例（50.8％）患者在完成12个计划的奥沙利铂周期之前过早退出。在MR309组中，由于癌症进展而过早停药的频率较低（7.4%vs安慰剂组25.0%；p=0.054）。MR309显着降低了冷痛阈温度[平均治疗效果差异（SE）与安慰剂：5.29（1.60）°C；p=0.001]和超阈值冷刺激诱发的疼痛强度[平均治疗效果差异：1.24（0.57）分；p=0.032]。神经病变总评分,与健康相关的生活质量措施，和神经传导参数的变化相似，在两个手臂，而在MR309组中,重度慢性神经病变患者(美国国家癌症研究所不良事件通用术语标准≥3)的比例显著较低(3.0%vs安慰剂组18.2%;p=0.046).在活动臂中递送的奥沙利铂的总量更大(1618.9mg对安慰剂的1453.8mg;p=0.049)。总的来说,19.0%的患者至少经历过1次与治疗相关的不良事件（MR309和安慰剂分别为25.8%和11.9%，分别)。使用MR309的间歇性治疗与急性奥沙林减少和奥沙利铂暴露增加相关。并显示了对慢性累积性奥沙伊普的潜在神经保护作用。此外，MR309显示出可接受的安全性。
