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首页> 外文期刊>British Journal of Cancer >A Phase I clinical and pharmacological study of cis-diamminedichloro(2-methylpyridine) platinum II (AMD473)
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A Phase I clinical and pharmacological study of cis-diamminedichloro(2-methylpyridine) platinum II (AMD473)

机译：顺二氨二氯（2-甲基吡啶）铂II（AMD473）的I期临床和药理研究

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AMD473 is a novel sterically hindered platinum cytotoxic with demonstrated ability to overcome acquired resistance to cisplatin in vitro and in human tumour xenografts. A single-agent dose escalating Phase I study was performed. AMD473 was initially administered intravenously as a 1?h infusion every 21 days to patients with advanced solid tumours. In total, 42 patients received a total of 147 cycles (median 3, range 1–8) of treatment at doses of 12, 24, 48, 96, 110, 120, 130, and 150?mg?m?2. Dosing intervals of 21 and 28 days were explored at the recommended dose. Neutropenia and thrombocytopenia proved dose limiting. Other toxicities included moderate nausea, vomiting, anorexia, and a transient metallic taste. There was no significant alopecia. The maximum tolerated dose was 150?mg?m?2. Plasma pharmacokinetics were linear. Two patients with heavily pretreated ovarian cancer showed partial response. Five patients (mesothelioma, ovary, nonsmall cell lung, and melanoma) showed prolonged stable disease. AMD473 demonstrates encouraging activity in patients, including those with prior platinum exposure. Toxicity is predictable with linear pharmacokinetics, as was predicted by preclinical studies. A dose of 120?mg?m?2 every 21 days is recommended for Phase II evaluation although there is evidence that chemo-naive patients and those of good performance status may tolerate a higher dose.
机译：AMD473是一种新型的位阻铂细胞毒性药物，具有在体外和人肿瘤异种移植物中克服获得的对顺铂耐药性的能力。进行了单药剂量递增的I期研究。最初将AMD473以每21天1小时的速度静脉输注给患有实体瘤的患者。总共有42例患者接受了12个，24个，48个，96个，110个，120个，130个和150 mg•m？2剂量的147个疗程（中位数3，范围1-8）。推荐剂量为21天和28天。中性粒细胞减少症和血小板减少症证明是剂量限制的。其他毒性包括中度恶心，呕吐，厌食和短暂的金属味。没有明显的脱发。最大耐受剂量为150？mg？m？2。血浆药代动力学是线性的。两名患有严重预处理卵巢癌的患者表现出部分反应。五例患者（间皮瘤，卵巢，非小细胞肺癌和黑色素瘤）表现出长期稳定的疾病。 AMD473表现出令人鼓舞的活动，包括先前有铂暴露的患者。正如临床前研究所预测的那样，线性药代动力学可以预测毒性。尽管有证据表明未接受过化学治疗的患者和表现良好的患者可以耐受更高的剂量，但建议每21天服用120？mg？m？2的剂量进行II期评估。

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