Phase 2 study of glucarpidase in patients with delayed methotrexate elimination after high-dose methotrexate therapy,Cancer Chemotherapy and Pharmacology

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Phase 2 study of glucarpidase in patients with delayed methotrexate elimination after high-dose methotrexate therapy
Cancer Chemotherapy and Pharmacology ( IF 2.7 ) Pub Date : 2024-03-13 , DOI: 10.1007/s00280-024-04664-6
Atsushi Ogawa ₁ , Hiroshi Kawamoto ₂ , Junichi Hara ₃ , Atsushi Kikuta ₄ , Chitose Ogawa ₅ , Hiroaki Hiraga ₆ , Kenichi Yoshimura ₇ , Kazunari Miyairi ₈ , Reiko Omori ₈ , Tokihiro Ro ₈ , Yuna Kamei ₈ , Toshimi Kimura ₉

Affiliation

Purpose

High-dose methotrexate therapy (HD-MTX) is a standard treatment for various malignant tumors, but approximately 1–10% of patients experience delayed MTX elimination (DME) that can induce organ damage. Glucarpidase can hydrolyze MTX and thereby lower the level of active MTX in the blood. A multicenter, open-label, phase II investigator-initiated trial (CPG2-PII study) was conducted to evaluate glucarpidase rescue therapy in Japanese patients who showed DME after HD-MTX treatment. To confirm the robustness of this therapy, further corporate-sponsored clinical trial (OP-07-001 study) was conducted.

Methods

The primary endpoint in the CPG2-PII study was to evaluate the proportion of patients of the percentage clinical important reduction (CIR) as an indicator of MTX concentration, which can be managed with leucovorin and supportive care. The primary endpoint of the OP-07-001 study was to evaluate the decreasing rate of plasma MTX concentration at 20 min after glucarpidase administration from the baseline for four patients. Glucarpidase was administered at a dose of 50 U/kg for 15 and 4 patients, respectively in the two studies, and safety was analyzed for each of them.

Results

The rate of CIR was 76.9% (95% confidence interval, 46.2–95.0%) in the CPG2-PII study. The median reduction rate of plasma MTX was 98.83% in the OP-07-001 study. Hypersensitivity, blood bilirubin increased, and headache for each patient were the only study drug-related events.

Conclusion

Glucarpidase showed an effect of reducing plasma MTX concentration in Japanese patients with DME as that observed in a previous US study, confirming its favorable safety and tolerability.

中文翻译：

葡萄糖醛蛋白酶在大剂量甲氨蝶呤治疗后延迟甲氨蝶呤消除患者中的 2 期研究

目的

大剂量甲氨蝶呤治疗（HD-MTX）是各种恶性肿瘤的标准治疗方法，但大约 1-10% 的患者会出现延迟的 MTX 消除（DME），这会导致器官损伤。葡萄糖醛蛋白酶可以水解 MTX，从而降低血液中活性 MTX 的水平。进行了一项多中心、开放标签、II 期研究者发起的试验（CPG2-PII 研究），以评估 HD-MTX 治疗后出现 DME 的日本患者的葡萄糖活性酶挽救治疗。为了证实这种疗法的稳健性，进行了进一步的企业赞助临床试验（OP-07-001 研究）。

方法

CPG2-PII 研究的主要终点是评估临床重要降低百分比（CIR）作为 MTX 浓度指标的患者比例，这可以通过亚叶酸和支持治疗进行管理。OP-07-001 研究的主要终点是评估 4 例患者在葡萄糖果蛋白酶给药后 20 min 血浆 MTX 浓度较基线下降的速率。在两项研究中，15 例和 4 例患者分别以 50 U/kg 的剂量施用葡萄糖果蛋白酶，并分析了每例患者的安全性。