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

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

doi:10.1007/s00280-020-04135-8

Abstract

PurposeThe 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).MethodsThis 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.ResultsSeventy-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.ConclusionART-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

Highlights

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 colorectal cancer as palliative chemotherapy [1,2,3,4].Oxaliplatin-induced peripheral neuropathy (OIPN) is a well-recognized, dose-limiting toxicity
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, and 32.3 with 3-day ART
Between July 2016 and April 2017, 87 participants were recruited from 11 hospitals in Japan, and 80 participants were randomly assigned to the placebo (n = 28), 1-day ART (n = 27), and 3-day ART (n = 25) arms (Fig. 1)

Summary

Introduction

Oxaliplatin-induced peripheral neuropathy (OIPN) is a well-recognized, dose-limiting toxicity. There are two types of neuropathy, acute and chronic (cumulative) neuropathy. Acute neuropathy symptoms including cold allodynia and muscle cramps are generally transient and mild, and they. Chronic neuropathy is problematic with the oxaliplatin-containing regimen, and its severity is correlated with the cumulative dosage of oxaliplatin [6]. Chronic OIPN is mainly a sensory neuropathy characterized by numbness, paresthesia, and allodynia; motor neuropathy is less frequent. Chronic OIPN lasts for months or even years after discontinuation of oxaliplatin, and it sometimes worsens transiently for a few months [9,10,11]. To relieve only painful OIPN, duloxetine is moderately recommended in the American Society of Clinical Oncology clinical practice guideline [12]

Methods

Results

Conclusion