Lowndes Sarah A, Adams Avril, Timms Anthony, Fisher Nita, Smythe Jon, Watt Suzanne M, Joel Simon, Donate Fernando, Hayward Carolyn, Reich Steven, Middleton Mark, Mazar Andrew, Harris Adrian L
Cancer Research UK Department of Medical Oncology, Churchill Hospital, Oxford, United Kingdom.
Clin Cancer Res. 2008 Nov 15;14(22):7526-34. doi: 10.1158/1078-0432.CCR-08-0315.
Copper chelation reduces the secretion of many angiogenic factors and reduces tumor growth and microvascular density in animal models. ATN-224 is a second-generation analogue of ammonium tetrathiomolybdate. The aim of our phase I study was to reduce serum copper levels, as measured by ceruloplasmin, to 5 to 15 mg/dL (normal 16-60) in 14 to 21 days, to determine the pharmacokinetic profile of ATN-224 and to evaluate dose-limiting toxicities.
Cohorts of patients were treated with escalating oral doses of ATN-224 until copper depletion followed by a titrated maintenance dose.
Eighteen patients received 78 cycles of ATN-224. Mean baseline ceruloplasmin was 39.6 mg/dL. The maximum administered dose was 330 mg/d where grade 3 fatigue was dose-limiting. At the maximum tolerated dose of 300 mg/d, the median time to achieve target ceruloplasmin was 21 days, and toxicities included grade 3 anemia, grade 3 neutropenia, fatigue, and sulfur eructation. ATN-224 treatment caused a significant reduction (> 90%) in RBC superoxide dismutase 1 activity and circulating endothelial cells. Pharmacokinetic data indicate greater absorption of ATN-224 and more rapid ceruloplasmin reduction when administered with a proton pump inhibitor. Stable disease of > 6 months was observed in 2 patients.
Oral ATN-224 is a well-tolerated therapy and at a loading dose of 300 mg/d leads to a reduction of serum ceruloplasmin levels in 80% patients within 21 days. A loading dose of 300 mg/d for 2 weeks followed by a titrated maintenance dose will be the recommended starting dose for phase II study.
在动物模型中，铜螯合可减少多种血管生成因子的分泌，并降低肿瘤生长和微血管密度。ATN - 224是四硫代钼酸铵的第二代类似物。我们I期研究的目的是在14至21天内将通过铜蓝蛋白测量的血清铜水平降至5至15mg/dL（正常为16 - 60），确定ATN - 224的药代动力学特征，并评估剂量限制性毒性。
患者队列接受递增口服剂量的ATN - 224治疗，直至铜耗竭，随后给予滴定维持剂量。
18名患者接受了78个周期的ATN - 224治疗。平均基线铜蓝蛋白为39.6mg/dL。最大给药剂量为330mg/d，其中3级疲劳为剂量限制性毒性。在最大耐受剂量300mg/d时，达到目标铜蓝蛋白的中位时间为21天，毒性包括3级贫血、3级中性粒细胞减少、疲劳和硫磺嗳气。ATN - 224治疗导致红细胞超氧化物歧化酶1活性和循环内皮细胞显著降低（>90%）。药代动力学数据表明，与质子泵抑制剂联合给药时，ATN - 224的吸收更好，铜蓝蛋白降低更快。2名患者观察到疾病稳定>6个月。
口服ATN - 224是一种耐受性良好的治疗方法，负荷剂量为300mg/d可使80%的患者在21天内血清铜蓝蛋白水平降低。II期研究的推荐起始剂量为负荷剂量30mg/d，持续2周，随后给予滴定维持剂量。
