Abstract
This trial assessed the efficacy of MR309 (a novel selective sigma-1 receptor ligand previously developed as E-52862) in ameliorating oxaliplatin-induced peripheral neuropathy (oxaipn). A discontinuous regimen of MR309 (400 mg/day, 5 days per cycle) was tested in patients with colorectal cancer receiving FOLFOX in a phase II, randomized, double-blind, placebo-controlled, multicenter clinical trial. Outcome measures included changes in 24-week quantitative measures of thermal sensitivity and total neuropathy score. In total, 124 patients were randomized (1:1) to MR309 or placebo. Sixty-three (50.8%) patients withdrew prematurely before completing 12 planned oxaliplatin cycles. Premature withdrawal because of cancer progression was less frequent in the MR309 group (7.4% vs 25.0% with placebo; p = 0.054). MR309 significantly reduced cold pain threshold temperature [mean treatment effect difference (SE) vs placebo: 5.29 (1.60)°C; p = 0.001] and suprathreshold cold stimulus-evoked pain intensity [mean treatment effect difference: 1.24 (0.57) points; p = 0.032]. Total neuropathy score, health-related quality-of-life measures, and nerve-conduction parameters changed similarly in both arms, whereas the proportion of patients with severe chronic neuropathy (National Cancer Institute Common Terminology Criteria for Adverse Events ≥ 3) was significantly lower in the MR309 group (3.0% vs 18.2% with placebo; p = 0.046). The total amount of oxaliplatin delivered was greater in the active arm (1618.9 mg vs 1453.8 mg with placebo; p = 0.049). Overall, 19.0% of patients experienced at least 1 treatment-related adverse event (25.8% and 11.9% with MR309 and placebo, respectively). Intermittent treatment with MR309 was associated with reduced acute oxaipn and higher oxaliplatin exposure, and showed a potential neuroprotective role for chronic cumulative oxaipn. Furthermore, MR309 showed an acceptable safety profile.
Highlights
Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent neurological complication of anticancer treatment and a common dose-limiting side effect [1]
The average number of cycles and the incidence of OXA dose reductions were similar in both groups, the total accumulated amount of OXA delivered was greater in the MR309 group
The selective sigma1 receptor (S1R) antagonist MR309 was able to partially preserve the cold pain threshold (CPT), reduce cold-evoked pain, and motor hyperexcitability signs and symptoms in patients with colorectal cancer treated with OXA
Summary
Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent neurological complication of anticancer treatment and a common dose-limiting side effect [1]. Oxaliplatin (OXA) is the cornerstone of colorectal cancer treatment [2] and is being increasingly used to treat other malignancies. Efficacy of a Novel Sigma-1 Receptor Antagonist for Oxaliplatin-Induced Neuropathy: A Randomized,. OXAIPN usually presents as 2 distinct clinical syndromes [4]. One is a classic cumulative, chronic sensory neuropathy, which involves typical features of platinum drug peripheral neuropathy. The other, more distinctive of OXA, is an acute transient syndrome characterized by paresthesias and dysesthesias triggered by exposure to cold in the distal extremities and the perioral region [5]. The acute syndrome can include a neuromyotonia-like syndrome, with motor hyperexcitability symptoms [1]
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