A placebo-controlled, double-blind, randomized study of recombinant thrombomodulin (ART-123) to prevent oxaliplatin-indu
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ORIGINAL ARTICLE
A placebo‑controlled, double‑blind, randomized study of recombinant thrombomodulin (ART‑123) to prevent oxaliplatin‑induced peripheral neuropathy Masahito Kotaka1 · Yoji Saito2 · Takeshi Kato3,4 · Hironaga Satake5,6 · Akitaka Makiyama7,8 · Yasushi Tsuji9 · Katsunori Shinozaki10 · Toshiyoshi Fujiwara11 · Tsunekazu Mizushima12 · Yasushi Harihara13 · Naoki Nagata14 · Naoto Kurihara15 · Masahiko Ando16 · Genichi Kusakawa17 · Takumi Sakai17 · Yugo Uchida17 · Mikihiro Takamoto17 · Saki Kimoto17 · Ichinosuke Hyodo18,19 Received: 2 April 2020 / Accepted: 4 September 2020 © The Author(s) 2020
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 leastsquares 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 Keywords CIPN · Neuropathy · Oxaliplatin · Adjuvant chemotherapy · Colon cancer · Thrombomodulin
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00280-020-04135-8) contains supplementary material, which is available to authorized users. * Masahito Kotaka [email protected] Extended author information available on the last page of the article
Oxaliplatin is a key drug in the treatment of colorectal cancer and is used in combination with 5-fluorouracil/leucovorin (FOLFOX) or capecitabine for resected stage III colon cancer as adjuvant chemotherapy and for metastatic colo
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