[Cu, Zn] 超氧化物歧化酶 (SOD1) 抑制剂 ATN-224（双胆碱四硫钼酸盐）在晚期血液系统恶性肿瘤患者 (pts) 中的 I 期研究。,Blood

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[Cu, Zn] 超氧化物歧化酶 (SOD1) 抑制剂 ATN-224（双胆碱四硫钼酸盐）在晚期血液系统恶性肿瘤患者 (pts) 中的 I 期研究。
Blood ( IF 21.0 ) Pub Date : 2006-11-16 , DOI: 10.1182/blood.v108.11.2593.2593
James R. Berenson ₁ , Ralph Vincent Boccia ₂ , Asad Bashey ₃ , Alexandra M. Levine ₄ , Omer N. Koc ₅ , Jennifer A. Callahan ₆ , Andrew P. Mazar ₆ , Steven D. Reich ₆

Affiliation

背景：ATN-224 是一种可口服的小分子，含有特异性结合铜的钼 (Mo)。ATN-224 抑制多种对血管生成和肿瘤生长很重要的信号通路，例如由生长因子介导的通路，包括血管内皮生长和表皮生长因子以及信号分子，如蛋白激酶 B (PKB/Akt) 和核因子 kappa B。 ATN- 224 通过抑制内皮细胞和肿瘤细胞中的铜锌超氧化物歧化酶 (SOD1) 来发挥这些作用。在包括硼替佐米抗性骨髓瘤在内的多种动物肿瘤模型中都观察到了这种活性。方法：纳入患有复发性或难治性血液系统恶性肿瘤或不存在标准治疗的成人患者。Pts 必须有足够的体能状态（PS 0-2），并且有足够的血液学和器官功能。监测患者的安全性和有效性，并在指定的时间间隔采集血样用于药代动力学和生物标志物测定。从 120 毫克/天开始，每个剂量水平至少招募 3 名患者。在 28 天前因毒性以外的原因离开研究的患者将被替换。如果 1 位患者出现了方案定义的剂量限制性毒性 (DLT)，则该队列将扩大至最多 6 位患者。最大耐受剂量 (MTD) 定义为 6 名患者中不超过 1 名患有 DLT 的最高剂量。根据毒性和血清铜蓝蛋白 (Cp)（全身铜的替代标志物）进行剂量调整。Pts 接受了 2 周的负荷剂量，然后滴定剂量以保持 Cp 在 5 和 15 mg/dL 之间。结果：17 名患者（53% 女性），年龄 43-79 岁（平均 63 岁），PS 0 或 1。8 名患者患有骨髓瘤，5 名白血病患者，3 名淋巴瘤患者和 1 名骨髓增生异常综合征。由于 5 名被替换的患者和 1 名 DLT（[Gr] 4 级中性粒细胞减少症，3 级贫血）的快速进展，11 名患者进入第一队列。根据对实体瘤患者进行的一项伴随研究的信息，下一组的剂量增加到 300 mg。6 名患者中有 1 名患有 DLT（4 级中性粒细胞减少症）。没有进入更多的队列，因为 300 毫克/天被确定为伴随研究的 MTD。发现接受长效抗酸剂的患者的钼浓度高于未接受的患者，因此对该方案进行了修改，要求所有患者每天接受抗酸剂。观察到红细胞（肿瘤的替代组织）中 SOD 的剂量依赖性抑制。主要不良事件包括可逆的 Gr 4 中性粒细胞减少症、Gr 3 贫血和 Gr 3 血小板减少症。在该试验中未观察到 Gr 3 疲劳，即实体瘤研究中的 DLT。还观察到轻度至中度症状，例如胃肠道疾病、头痛和头晕。没有反应，但 1 名白血病患者病情稳定 5 个月，一名骨髓瘤患者病情稳定 4.5 个月。结论：ATN-224 是一种具有新作用机制的抗血管生成和抗肿瘤剂，具有可控、可逆的毒性。II 期研究的推荐剂量为 300 毫克/天，从 2 周开始调整剂量以将 Cp 维持在 5-15 毫克/分升。主要不良事件包括可逆的 Gr 4 中性粒细胞减少症、Gr 3 贫血和 Gr 3 血小板减少症。在该试验中未观察到 Gr 3 疲劳，即实体瘤研究中的 DLT。还观察到轻度至中度症状，例如胃肠道疾病、头痛和头晕。没有反应，但 1 名白血病患者病情稳定 5 个月，一名骨髓瘤患者病情稳定 4.5 个月。结论：ATN-224 是一种具有新作用机制的抗血管生成和抗肿瘤剂，具有可控、可逆的毒性。II 期研究的推荐剂量为 300 毫克/天，从 2 周开始调整剂量以将 Cp 维持在 5-15 毫克/分升。主要不良事件包括可逆的 Gr 4 中性粒细胞减少症、Gr 3 贫血和 Gr 3 血小板减少症。在该试验中未观察到 Gr 3 疲劳，即实体瘤研究中的 DLT。还观察到轻度至中度症状，例如胃肠道疾病、头痛和头晕。没有反应，但 1 名白血病患者病情稳定 5 个月，一名骨髓瘤患者病情稳定 4.5 个月。结论：ATN-224 是一种具有新作用机制的抗血管生成和抗肿瘤剂，具有可控、可逆的毒性。II 期研究的推荐剂量为 300 毫克/天，从 2 周开始调整剂量以将 Cp 维持在 5-15 毫克/分升。在本次试验中未观察到。还观察到轻度至中度症状，例如胃肠道疾病、头痛和头晕。没有反应，但 1 名白血病患者病情稳定 5 个月，一名骨髓瘤患者病情稳定 4.5 个月。结论：ATN-224 是一种具有新作用机制的抗血管生成和抗肿瘤剂，具有可控、可逆的毒性。II 期研究的推荐剂量为 300 毫克/天，从 2 周开始调整剂量以将 Cp 维持在 5-15 毫克/分升。在本次试验中未观察到。还观察到轻度至中度症状，例如胃肠道疾病、头痛和头晕。没有反应，但 1 名白血病患者病情稳定 5 个月，一名骨髓瘤患者病情稳定 4.5 个月。结论：ATN-224 是一种具有新作用机制的抗血管生成和抗肿瘤剂，具有可控、可逆的毒性。II 期研究的推荐剂量为 300 毫克/天，从 2 周开始调整剂量以将 Cp 维持在 5-15 毫克/分升。一种具有新作用机制的抗血管生成和抗肿瘤剂，具有可控、可逆的毒性。II 期研究的推荐剂量为 300 毫克/天，从 2 周开始调整剂量以将 Cp 维持在 5-15 毫克/分升。一种具有新作用机制的抗血管生成和抗肿瘤剂，具有可控、可逆的毒性。II 期研究的推荐剂量为 300 毫克/天，从 2 周开始调整剂量以将 Cp 维持在 5-15 毫克/分升。

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Phase I Study of the [Cu, Zn] Superoxide Dismutase (SOD1) Inhibitor ATN-224 (Bis-Choline Tetrathiomolybdate) in Patients (pts) with Advanced Hematologic Malignancies.

BACKGROUND: ATN-224 is an orally available, small molecule containing molybdenum (Mo) that specifically binds copper. ATN-224 inhibits multiple signaling pathways important to angiogenesis and tumor growth such as pathways mediated by growth factors, including vascular endothelial growth and epidermal growth factors and signaling molecules such as protein kinase B (PKB/Akt) and nuclear factor kappa B. ATN-224 exerts these effects through the inhibition of the enzyme copper-zinc superoxide dismutase (SOD1) in endothelial and tumor cells. Activity has been seen in a variety of animal tumor models including bortezomib-resistant myeloma. METHODS: Adult pts with recurrent or refractory hematologic malignanies or for which no standard therapy exists were enrolled. Pts had to have adequate performance status (PS 0–2) and have adequate hematologic and organ function. Pts were monitored for safety and efficacy and blood samples for pharmacokinetic and biomarker determinations were taken at specified intervals. At least 3 pts were to be enrolled at each dose level starting at 120 mg/day. Pts who left the study prior to 28 days for reasons other than toxicity were to be replaced. If 1 pt developed dose-limiting toxicity (DLT) as defined by the protocol, the cohort was to be expanded to up to 6 pts. Maximum tolerated dose (MTD) was defined as the highest dose where no more than 1 of 6 pts had DLT. Dose adjustments were made on the basis of toxicity and serum ceruloplasmin (Cp), a surrogate marker for total body copper. Pts received a loading dose for 2 weeks and then doses were titrated to keep Cp between 5 and 15 mg/dL. RESULTS: 17 pts (53% female), ages 43–79 (mean 63), with PS 0 or 1 were entered. 8 pts had myeloma, 5 leukemia, 3 lymphoma, and 1 myelodysplastic syndrome. Because of rapid progression in 5 pts who were replaced and 1 DLT (Grade [Gr] 4 neutropenia, Gr 3 anemia), 11 pts were entered in the 1 st cohort. With information from a companion study in pts with solid tumors, the dose for the next cohort was increased to 300 mg. 1 of 6 pts had DLT (Gr 4 neutropenia). No further cohorts were entered as 300 mg/day was determined as MTD from the companion study. Pts who received long-acting antacids were found to have higher Mo concentrations than those without, so the protocol was amended to require all pts to receive daily antacid. Dose-dependent inhibition of SOD in red blood cells (a surrogate tissue for tumor) was observed. Major adverse events included reversible Gr 4 neutropenia, Gr 3 anemia, and Gr 3 thrombocytopenia. Gr 3 fatigue, which was DLT in the solid tumor study, was not observed in this trial. Mild to moderate symptoms such as gastrointestinal disorders, headache and lightheadedness were also observed. There were no responses but 1 pt with leukemia had stable disease for 5 months and a pt with myeloma had stable disease for 4.5 months. CONCLUSION: ATN-224, an antiangiogenesis and antitumor agent with a novel mechanism of action, has manageable, reversible toxicity. The dose recommended for Phase II studies is 300 mg/day with dose adjustment starting at 2 weeks to maintain Cp at 5–15 mg/dL.

更新日期：2006-11-16

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