Kotaka Masahito, Saito Yoji, Kato Takeshi, Satake Hironaga, Makiyama Akitaka, Tsuji Yasushi, Shinozaki Katsunori, Fujiwara Toshiyoshi, Mizushima Tsunekazu, Harihara Yasushi, Nagata Naoki, Kurihara Naoto, Ando Masahiko, Kusakawa Genichi, Sakai Takumi, Uchida Yugo, Takamoto Mikihiro, Kimoto Saki, Hyodo Ichinosuke
Gastrointestinal Cancer Center, Sano Hospital, 2-5-1 Shimizugaoka, Tarumi-ku, Kobe-shi, Hyogo, 655-0031, Japan.
Department of Anesthesiology, Shimane University Faculty of Medicine, 89-1 Enyacho, Izumo City, Shimane, 693-8501, Japan.
Cancer Chemother Pharmacol. 2020 Nov;86(5):607-618. doi: 10.1007/s00280-020-04135-8. Epub 2020 Sep 23.
The purpose of this clinical study was to be the first to explore whether ART-123, a recombinant human soluble thrombomodulin, prevents oxaliplatin-induced peripheral neuropathy (OIPN).
This randomized, phase IIa trial enrolled stage II/III colon cancer patients who received adjuvant mFOLFOX6 chemotherapy. Participants were randomly allocated to 3 arms in a double-blind manner: placebo (placebo: days 1-3); 1-day ART (ART-123: day 1, placebo: days 2-3); and 3-day ART (ART-123: days 1-3). ART-123 (380 U/kg/day) or placebo was infused intravenously before each 2-week cycle of mFOLFOX6. OIPN was assessed with the Functional Assessment of Cancer Therapy/Gynecological Oncology Group-Neurotoxicity-12 (FACT/GOG-Ntx-12) score by participants and the NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE) by investigators.
Seventy-nine participants (placebo n = 28, 1-day ART n = 27, 3-day ART n = 24) received study drugs. The least-squares mean FACT/GOG-Ntx-12 scores at cycle 12 from the mixed effect model for repeated measures were 28.9 with placebo, 36.3 with 1-day ART (vs. placebo: 7.3 [95% CI 1.9 to12.8, p = 0.009]), and 32.3 with 3-day ART (vs. placebo: 3.4 [95% CI -.1 to 9.0, p = 0.222]). The cumulative incidence of NCI-CTCAE grade ≥ 2 sensory neuropathy at cycle 12 was 64.3% with placebo, 40.7% with 1-day ART (vs. placebo: -23.5 [95% CI -48.4 to 4.0], p = 0.108), and 45.8% with 3-day ART (vs. placebo: -18.5 [95% CI -44.2 to 9.4], p = 0.264). Common adverse events were consistent with those reported with mFOLFOX6; no severe bleeding adverse events occurred.
ART-123 showed a potential preventive effect against OIPN with good tolerability. A larger study with 1-day ART is warranted. NCT02792842, registration date: June 8, 2016.
本临床研究旨在率先探索重组人可溶性血栓调节蛋白ART-123是否能预防奥沙利铂引起的周围神经病变（OIPN）。
本随机IIa期试验纳入接受辅助性mFOLFOX6化疗的II/III期结肠癌患者。参与者以双盲方式随机分为3组：安慰剂组（安慰剂：第1 - 3天）；1天ART组（ART-123：第1天，安慰剂：第2 - 3天）；和3天ART组（ART-123：第1 - 3天）。在每2周的mFOLFOX6化疗周期前静脉输注ART-123（380 U/kg/天）或安慰剂。参与者通过癌症治疗功能评估/妇科肿瘤学组-神经毒性-12（FACT/GOG-Ntx-12）评分评估OIPN，研究者通过美国国立癌症研究所不良事件通用术语标准（NCI-CTCAE）进行评估。
79名参与者（安慰剂组n = 28，1天ART组n = 27，3天ART组n = 24）接受了研究药物。重复测量混合效应模型在第12周期时的最小二乘均值FACT/GOG-Ntx-12评分，安慰剂组为28.9，1天ART组为36.3（与安慰剂组相比：7.3 [95% CI 1.9至12.8，p = 0.009]），3天ART组为32.3（与安慰剂组相比：3.4 [95% CI -0.1至9.0，p = 0.222]）。第12周期时NCI-CTCAE≥2级感觉神经病变的累积发生率，安慰剂组为64.3%，1天ART组为40.7%（与安慰剂组相比：-23.5 [95% CI -48.4至4.0]，p = 0.108），3天ART组为45.8%（与安慰剂组相比：-18.5 [95% CI -44.2至9.4]，p = 0.264）。常见不良事件与mFOLFOX6报道的一致；未发生严重出血不良事件。
ART-123对OIPN显示出潜在预防作用且耐受性良好。有必要对1天ART方案进行更大规模研究。NCT02792842，注册日期：2016年6月8日。
