Department of Oncology, Odense University Hospital, Odense, Denmark.
Smilow Cancer Hospital and Yale Cancer Center, Yale Medicine, New Haven, CT, USA.
JNCI Cancer Spectr. 2022 Nov 1;6(6). doi: 10.1093/jncics/pkac075.
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.
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.
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%).
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.
在转移性结直肠癌患者中进行的一项随机 2 期研究表明，钙敏化剂（CaM，PledOx）可有效预防患者报告的化疗诱导的周围神经病（CIPN）。预防奥沙利铂诱导的周围神经病变（POLAR）计划旨在评估 CaM 在接受奥沙利铂辅助（POLAR-A，ClinicalTrials.gov.NCT04034355）或转移性（POLAR-M，ClinicalTrials.gov.NCT03654729）治疗的患者中预防 CIPN 的疗效和安全性。
两项随机、安慰剂对照的 3 期试验研究了在开始使用亚叶酸、5-氟尿嘧啶和奥沙利铂治疗后 9 个月时患者报告的中重度 CIPN，这些试验中 CaM 与安慰剂联合使用。在 POLAR-A 中，III 期或高危 II 期结直肠癌患者被随机分配 1:1 接受 CaM 5μmol/kg 或安慰剂。在 POLAR-M 中，转移性结直肠癌患者被随机分配 1:1:1 接受 CaM 5μmol/kg、CaM 2μmol/kg 或安慰剂。
在 CaM 治疗患者中出现意外过敏反应后，POLAR-A（n=301）和 POLAR-M（n=291）提前终止。在两项试验的 9 个月 CIPN（主要终点）数据的联合分析中（CaM 5μmol/kg，n=175；安慰剂，n=176），与安慰剂组相比，CaM 组中有 54.3%的患者发生中重度 CIPN。9 个月时中重度 CIPN 的估计相对风险为 1.37（95%置信区间为 1.01 至 1.86；P=0.045）。与安慰剂组（0.8%）相比，接受 CaM 治疗的患者在两项试验中经历严重过敏反应的比例更高（3.6%）。
POLAR 临床研究未能达到主要终点。这些结果强调了在辅助和转移性环境中针对氧化应激预防 CIPN 的挑战性。
