Persistent prevention of oxaliplatin-induced peripheral neuropathy using calmangafodipir (PledOx^®): a placebo-controlled randomised phase II study (PLIANT)

Abstract

Purpose: Oxaliplatin causes disabling acute and chronic peripheral neuropathy. We explored the preventive effects of calmangafodipir, mimicking the mitochondrial enzyme manganese superoxide dismutase, thereby protecting cells from oxidative stress, in a placebo-controlled, double-blinded randomised phase II study (ClinicalTrials.gov.NCT01619423) in patients with metastatic colorectal cancer (mCRC).

Patient and methods: mCRC patients treated with modified FOLFOX-6 (folinic acid 200 mg/m², 5-fluorouracil bolus 400 mg/m², oxaliplatin 85 mg/m² and 5-fluorouracil 2400 mg/m² continuous infusion for 46 h) every fortnight for 8 cycles in first or second line were eligible. Calmangafodipir was given in a phase I dose-finding and in a phase II placebo-controlled study, as a 5-min infusion 10 min prior to oxaliplatin. Neurotoxicity was evaluated by the physician using the Oxaliplatin Sanofi Specific Scale and by the patient using the cold allodynia test and the Leonard scale.

Results: Eleven patients were included in phase I without any detectable toxicity to calmangafodipir. In the phase II study, 173 patients were randomised to placebo (n = 60), calmangafodipir 2 µmol/kg (n = 57) and calmangafodipir 5 µmol/kg (n = 45, initially 10 µmol/kg, n = 11). Calmangafodipir-treated patients (all three doses pooled) had less physician graded neurotoxicity (odds ratio (90% confidence interval one-sided upper level) 0.62(1.15), p = .16), significantly less problems with cold allodynia (mean 1.6 versus 2.3, p < .05) and significantly fewer sensory symptoms in the Leonard scale (cycle 1–8 mean 1.9 versus 3.0, p < .05 and during follow-up after 3 and 6 months, mean 3.5 versus 7.3, p < .01). Response rate, progression-free and overall survival did not differ among groups.

Conclusions: Calmangafodipir at a dose of 5 µmol/kg appears to prevent the development of oxaliplatin-induced acute and delayed CIPN without apparent influence on tumour outcomes.

Acknowledgments

The participation of the following investigators is acknowledged: Bulgaria: UMHAT Tzaritza Joanna‐ISUL EAD, Sofia, Asen Dudov; Complex Oncology Center‐Shumen EOOD, Shumen, Miglena Petrova; MHAT Serdika EOOD, Sofia, Krasimir Koynov; SHATO EAD, Sofia, Galina Kurteva; Complex Oncology Center EOOD, Plovdiv, Antoaneta Tomova. Denmark: Odense University Hospital, Odense, Per Pfeiffer; Aalborg University Hospital, Aalborg, Mette Yilmaz. Georgia: LTD High Technology Medical Center University Clinic, Tbilisi, Baadur Mosidze; LTD Clinic Medina, Batumi, Memed Jincharadze; JSC “Neo Medi”, Tbilisi, Mikheil Shavdia; S. Khechinashvili University Hospital, Tbilisi, Giorgi Dzagnidze; Research Institute of Clinical Medicine, Tbilisi, Tamar Melkadze. Germany: St. Josef‐Hospital ‐Universitätsklinik Ruhr – Universität Bochum, Anke Reinacher‐Schick; HELIOS Klinikum Wuppertal, Wuppertal, Oliver Schmalz; BAG Freiberg-Richter, Dresden, Lutz Jacobasch. Portugal: Centro Hospitalar do Baixo Vouga, Aveiro, Juan Carlos Mellidez; Hospital de Braga, Braga, Catarina Portela; Instituto Português Oncologia do Porto, Porto, Dânia Marques. Serbia: Inst Oncology and Radiology of Serbia, Belgrade, Davorin Radosavljevic; Military Medical Academy, Belgrade, Nebojsa Manojlovic; Clinical Hospital Center Zemun, Belgrade, Ljiljana Tomasic; Clinical Center Kragujevac, Kragujevac, Jasmina Nedovic. Sweden: University Hospital, Uppsala, Bengt Glimelius, Peter Nygren, Åke Berglund; Karolinska University Hospital, Stockholm, Mia Karlberg; University Hospital, Linköping, Johan Haux; University Hospital Sahlgrenska/Östra, Gothenburg, Susanne Ottosson; Gävle Hospital, Gävle, Marie Zajicova. USA: The University of Texas, Health Science Center, San Antonio TX, Devalingam Mahalingam; Associates in Oncology & Haematology Chattanooga, TN, Jitendra Gandhi; Benaroya Research Institute at Virginia Mason, Seattle, WA, Bruce Lin; Moores UCSD Cancer Center, La Jolla CA, Eric Roeland; Center for Cancer and Blood Disorders Bethesda, Ralph Boccia.

Disclosure statement

Bengt Glimelius, Consulting or advisory role, PledPharma AB; Devalingham Mahalingam, Honoraria, Consulting, PledPharma AB; Peter Buhl Jensen, Employment, Leadership, Stock, Honoraria, Buhl Pharma and PledPharma AB; Jan Kowalski, Consulting, PledPharma AB; Marie Bengtson, Employment, Stock, PledPharma AB; Malin Nittve, Employment, Stock, PledPharma AB; Jacques Näsström, Employment, Leadership, Stock, Patent, PledPharma AB. Remaining authors have declared no conflicts of interest.

Additional information

Funding

This study was financially supported by PledPharma AB, Stockholm, Sweden.