Calmangafodipir for Prevention of Oxaliplatin-Induced Peripheral Neuropathy: Two Placebo-Controlled, Randomized Phase 3 Studies (POLAR-A/POLAR-M).

Tytuł:: Calmangafodipir for Prevention of Oxaliplatin-Induced Peripheral Neuropathy: Two Placebo-Controlled, Randomized Phase 3 Studies (POLAR-A/POLAR-M).
Autorzy:: Pfeiffer P; Department of Oncology, Odense University Hospital, Odense, Denmark.
Lustberg M; Smilow Cancer Hospital and Yale Cancer Center, Yale Medicine, New Haven, CT, USA.
Näsström J; Egetis Therapeutics AB, Stockholm, Sweden.
Carlsson S; Egetis Therapeutics AB, Stockholm, Sweden.
Persson A; Egetis Therapeutics AB, Stockholm, Sweden.
Nagahama F; Solasia Pharma K.K., Tokyo, Japan.
Cavaletti G; Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
Glimelius B; Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Muro K; Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
Źródło:: JNCI cancer spectrum [JNCI Cancer Spectr] 2022 Nov 01; Vol. 6 (6).
Typ publikacji:: Clinical Trial, Phase III; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: Oxford : Oxford University Press, [2017]-
MeSH Terms:: Colorectal Neoplasms*/drug therapy
Colorectal Neoplasms*/pathology
Peripheral Nervous System Diseases*/chemically induced
Peripheral Nervous System Diseases*/drug therapy
Humans ; Oxaliplatin/adverse effects
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Grant Information:: UL1 TR001863 United States TR NCATS NIH HHS
Molecular Sequence:: ClinicalTrials.gov NCT03654729; NCT04034355
Substance Nomenclature:: P28BIW0UTB (N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid)
04ZR38536J (Oxaliplatin)
Entry Date(s):: Date Created: 20221029 Date Completed: 20221201 Latest Revision: 20230325
Update Code:: 20240105
PubMed Central ID:: PMC9678401
DOI:: 10.1093/jncics/pkac075
PMID:: 36308441
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Background: Calmangafodipir (CaM, PledOx) demonstrated efficacy in preventing patient-reported chemotherapy-induced peripheral neuropathy (CIPN) in a randomized phase 2 study in patients with metastatic colorectal cancer. The Preventive Treatment of OxaLiplatin Induced peripherAl neuRopathy (POLAR) program aimed to assess efficacy and safety of CaM in the prevention of CIPN in patients treated with oxaliplatin in adjuvant (POLAR-A, ClinicalTrials.gov.NCT04034355) or metastatic (POLAR-M, ClinicalTrials.gov.NCT03654729) settings.
Methods: Two randomized, placebo-controlled phase 3 trials investigated patient-reported, moderate-to-severe CIPN 9 months after beginning folinic acid, 5-fluorouracil, and oxaliplatin therapy with or without CaM. In POLAR-A, patients with stage III or high-risk stage II colorectal cancer were randomly assigned 1:1 to receive CaM 5 μmol/kg or placebo. In POLAR-M, patients with metastatic colorectal cancer were randomly assigned 1:1:1 to receive CaM 5 μmol/kg, CaM 2 μmol/kg, or placebo.
Results: POLAR-A (n = 301) and POLAR-M (n = 291) were terminated early following unexpected hypersensitivity reactions in CaM-treated patients. In a combined analysis of month 9 CIPN (primary endpoint) data from both trials (CaM 5 μmol/kg, n = 175; placebo, n = 176), 54.3% of patients in the CaM group had moderate-to-severe CIPN compared with 40.3% in the placebo group. The estimated relative risk for moderate-to-severe CIPN at month 9 was 1.37 (95% confidence interval = 1.01 to 1.86; P = .045). A higher proportion of patients experienced serious hypersensitivity reactions across both trials with CaM treatment (3.6%) than with placebo (0.8%).
Conclusion: The POLAR clinical studies failed to meet their primary endpoint. These results highlight the challenges of targeting oxidative stress for preventing CIPN in both the adjuvant and metastatic settings.
(© The Author(s) 2022. Published by Oxford University Press.)

Comment in: JNCI Cancer Spectr. 2022 Nov 1;6(6):. (PMID: 36308449)

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