Journal Article

Efficacy of a Novel Sigma-1 Receptor Antagonist for Oxaliplatin-Induced Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Clinical Trial

Alberti, Paola, Bruna, Jordi, Cortinovis, Diego, Cavaletti, Guido, Briani, Chiara, Nadal, Cristina, Kalofonos, Haralabos P., Vaqué, Anna, Videla, Sebastián, Sust, Mariano, Klein, Thomas, Villoria, Jesús, Argyriou, Andreas A., Santos, Cristina, Velasco, Roser, Plata-Salamán, Carlos

2018

Overview

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.

• Publisher: Elsevier Inc,Springer US,Springer Nature B.V
• Subject: Adult / Adverse effects / Aged / Antineoplastic Agents - adverse effects / Biomedical and Life Sciences / Biomedicine / Cancer / Chemotherapy / Clinical trials / Cold stimuli / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - complications / Colorectal Neoplasms - drug therapy / Double-Blind Method / Double-blind studies / Female / Humans / Male / Middle Aged / Morpholines - therapeutic use / MR309/E-52862 / Nerve conduction / Neurobiology / Neurology / Neuropathic pain / Neuroprotection / Neurosciences / Neurosurgery / Neurotoxicity / Original / Original Article / Oxaliplatin / Oxaliplatin - adverse effects / Pain perception / Pain Threshold - drug effects / Peripheral Nervous System Diseases - chemically induced / Peripheral Nervous System Diseases - drug therapy / Peripheral neuropathy / Pyrazoles - therapeutic use / Receptors, sigma - antagonists & inhibitors / Sigma-1 Receptor / Terminology / Treatment Outcome / Young Adult