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Open Access 01-11-2020 | Colon Cancer | Original Article

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

Authors: Masahito Kotaka, Yoji Saito, Takeshi Kato, Hironaga Satake, Akitaka Makiyama, Yasushi Tsuji, Katsunori Shinozaki, Toshiyoshi Fujiwara, Tsunekazu Mizushima, Yasushi Harihara, Naoki Nagata, Naoto Kurihara, Masahiko Ando, Genichi Kusakawa, Takumi Sakai, Yugo Uchida, Mikihiro Takamoto, Saki Kimoto, Ichinosuke Hyodo

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2020

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 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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Title: A placebo-controlled, double-blind, randomized study of recombinant thrombomodulin (ART-123) to prevent oxaliplatin-induced peripheral neuropathy
Authors: Masahito Kotaka
Yoji Saito
Takeshi Kato
Hironaga Satake
Akitaka Makiyama
Yasushi Tsuji
Katsunori Shinozaki
Toshiyoshi Fujiwara
Tsunekazu Mizushima
Yasushi Harihara
Naoki Nagata
Naoto Kurihara
Masahiko Ando
Genichi Kusakawa
Takumi Sakai
Yugo Uchida
Mikihiro Takamoto
Saki Kimoto
Ichinosuke Hyodo
Publication date: 01-11-2020
Publisher: Springer Berlin Heidelberg
Keywords: Colon Cancer
Colon Cancer
Cytostatic Therapy
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2020
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-020-04135-8

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