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

Per Pfeiffer, Maryam Lustberg, Jacques Näsström, Stefan Carlsson, Anders Persson, Fumiko Nagahama, Guido Cavaletti, Bengt Glimelius, Kei Muro, Per Pfeiffer, Maryam Lustberg, Jacques Näsström, Stefan Carlsson, Anders Persson, Fumiko Nagahama, Guido Cavaletti, Bengt Glimelius, Kei Muro

Abstract

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.

Figures

Figure 1.
Figure 1.
Study design. CaM = calmangafodipir; CIPN = chemotherapy-induced peripheral neuropathy; mFOLFOX6 = modified folinic acid, 5-fluorouracil, and oxaliplatin chemotherapy regimen; POLAR-A = Preventive Treatment of OxaLiplatin Induced peripherAl neuRopathy in adjuvant setting; POLAR-M = Preventive Treatment of OxaLiplatin Induced peripherAl neuRopathy in metastatic setting.
Figure 2.
Figure 2.
Patient flow. CaM = calmangafodipir; mITT = modified intention-to-treat; POLAR-A = Preventive Treatment of OxaLiplatin Induced peripherAl neuRopathy in adjuvant setting; POLAR-M = Preventive Treatment of OxaLiplatin Induced peripherAl neuRopathy in metastatic setting.
Figure 3.
Figure 3.
Proportion of patients in the POLAR studies with moderate-to-severe chemotherapy-induced peripheral neuropathy by treatment and visit (combined mITT set). These patients had a score of 3 or 4 on at least 1 of the first 4 items of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity 13-item subscale at each treatment visit (cycle) and at 9 months (primary endpoint). C = cycle; CaM = calmangafodipir; mITT = modified intention-to-treat; POLAR = Preventive Treatment of OxaLiplatin Induced peripherAl neuRopathy.

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Source: PubMed

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