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A placebo-controlled, double-blind, randomized study of recombinant thrombomodulin (ART-123) to prevent oxaliplatin-induced peripheral neuropathy.

Gastrointestinal Cancer Center, Sano Hospital, 2-5-1 Shimizugaoka, Tarumi-ku, Kobe-shi, Hyogo, 655-0031, Japan. tomomakotaka6410@yahoo.co.jp. Department of Anesthesiology, Shimane University Faculty of Medicine, 89-1 Enyacho, Izumo City, Shimane, 693-8501, Japan. Department of Gastroenterological Surgery, Kansai Rosai Hospital, 3-1-69 Inabaso, Amagasaki-shi, Hyogo, 660-8511, Japan. Colorectal Surgery, National Hospital Organization Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka City, Osaka, 540-0006, Japan. Department of Medical Oncology, Kobe City Medical Center General Hospital, 2-1-1 Minatojimaminamimachi, Chuo-ku, Kobe-city, Hyogo, 650-0047, Japan. Cancer Treatment Center, Kansai Medical University Hospital, 2-3-1 Shin-machi, Hirakata City, Osaka, 573-1191, Japan. Department of Hematology/Oncology, Japan Community Healthcare Organization Kyushu Hospital, 1-8-1 Kishinoura, Yahatanishi-ku, Kitakyusyu-shi, Fukuoka, 806-8501, Japan. Cancer Center, Gifu University Hospital, 1-1 Yanagido, Gifu, 501-1194, Japan. Department of Medical Oncology, Tonan Hospital, Kita 4-jo Nishi 7-chome 3-8, Chuo-ku, Sapporo-shi, Hokkaido, 060-0004, Japan. Division of Clinical Oncology, Hiroshima Prefectural Hospital, 1-5-54 Ujinakanda, Minami-ku, Hiroshima-shi, Hiroshima, 734-8530, Japan. Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama-city, Okayama, 700-8558, Japan. Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. Department of Surgery, NTT Medical Center Tokyo, 5-9-22 Higashi-Gotanda, Shinagawa-ku, Tokyo, 141-8625, Japan. Department of Surgery, Kitakyushu General Hospital, 1-1 Higashijono-machi, Kokurakita-ku, Kitakyushu, 802-8517, Japan. Department of Surgery, Nerima General Hospital, 1-24-1 Asahigaoka, Nerima-ku, Tokyo, 176-8530, Japan. Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan. Clinical Development Center, Asahi Kasei Pharma Corporation, 1-1-2 Yurakucho, Chiyoda-ku, Tokyo, 100-0006, Japan. Division of Gastroenterology, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan. Division of Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, 160 Kou Minami-umemoto, Matsuyama-city, Ehime, 791-0280, Japan.

Cancer chemotherapy and pharmacology. 2020;(5):607-618
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Abstract

PURPOSE 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). METHODS 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. RESULTS 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. CONCLUSION 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.

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