Bengt Glimelius1, Nebojsa Manojlovic2, Per Pfeiffer3, Baadur Mosidze4, Galina Kurteva5, Mia Karlberg6, Devalingam Mahalingam7, Peter Buhl Jensen8,9, Jan Kowalski10, Marie Bengtson9, Malin Nittve9, Jacques Näsström9. 1. a Department of Immunology, Genetics and Pathology , Uppsala University , Uppsala , Sweden. 2. b Clinic for Gastroenterology and Hepatology of Military Medical Academy of Serbia , Belgrade , Serbia. 3. c Department of Oncology , Odense University Hospital , Odense , Denmark. 4. d LTD High Technology Medical Center, University Clinic , Tbilisi , Georgia. 5. e Clinic of Chemotherapy, SHATO EAD , Sofia , Bulgaria. 6. f Department of Oncology and Pathology , Karolinska Institutet , Stockholm , Sweden. 7. g Cancer Therapy and Research Center , The University of Texas Health Science Center San Antonio , San Antonio , TX , USA. 8. h Buhl Oncology , Copenhagen , Denmark. 9. i PledPharma AB , Stockholm , Sweden. 10. j JK Biostatistics , Stockholm , Sweden.
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 withmodified 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.
RCT Entities:
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.
Authors: Shuiying Hu; Kevin M Huang; Elizabeth J Adams; Charles L Loprinzi; Maryam B Lustberg Journal: Clin Cancer Res Date: 2019-05-23 Impact factor: 12.531
Authors: Jessica N Mezzanotte; Michael Grimm; Namrata V Shinde; Timiya Nolan; Lise Worthen-Chaudhari; Nicole O Williams; Maryam B Lustberg Journal: Curr Treat Options Oncol Date: 2022-02-15
Authors: Emma E Morrison; Katherine Oatey; Bernadette Gallagher; Julia Grahamslaw; Rachel O'Brien; Polly Black; Wilna Oosthuyzen; Robert J Lee; Christopher J Weir; Dennis Henriksen; James W Dear Journal: EBioMedicine Date: 2019-07-13 Impact factor: 8.143