AZD1480: A Phase I Study of a Novel JAK2 Inhibitor in Solid Tumors. (11th July 2013)

• Record Type: Journal Article
• Authors: Plimack, Elizabeth R.; LoRusso, Patricia M.; McCoon, Patricia; Tang, Weifeng; Krebs, Annetta D.; Curt, Gregory; Eckhardt, S. Gail
• Is Part Of: Oncologist. Volume 18:Number 7(2013)
• Page Start: 819
• Page End: 820
• Publication Date: 2013-07-11
• Subjects: Oncology -- Periodicals; Tumors -- Periodicals; Cancérologie -- Périodiques; Tumeurs -- Périodiques; Oncology; Tumors; Neoplasms; Electronic journals; Periodicals; Periodicals; 616.994
• DOI: 10.1634/theoncologist.2013-0198
• Languages: English
• ISSNs: 1083-7159

Abstract

Abstract : Background: AZD1480 is a novel agent that inhibits Janus‐associated kinases 1 and 2 (JAK1 and JAK2). The primary objective of this phase I study was to investigate the safety and tolerability of AZD1480 when administered as monotherapy to patients with solid tumors. Methods: Thirty‐eight patients with advanced malignancies were treated at doses of 10–70 mg once daily (QD) and 20–45 mg b.i.d. Results: Pharmacokinetic (PK) analysis revealed rapid absorption and elimination with minimal accumulation after repeated QD or b.i.d. dosing. Exposure increased in a dose‐dependent manner from 10–50 mg. Maximum plasma concentration (Cmax ) was attained ∼1 hour after dose, and t1/2 was ∼5 hours. Pharmacodynamic analysis of circulating granulocytes demonstrated maximum phosphorylated STAT3 (pSTAT3) inhibition 1–2 hours after dose, coincident with Cmax, and greater pSTAT3 inhibition at higher doses. The average pSTAT3 inhibition in granulocytes at the highest dose tested, 70 mg QD, was 56% (standard deviation: ±21%) at steady‐state drug levels. Dose‐limiting toxicities (DLTs) consisted of pleiotropic neurologic adverse events (AEs), including dizziness, anxiety, ataxia, memory loss, hallucinations, and behavior changes. These AEs were generally reversible with dose reduction or treatment cessation. Conclusions: Whether the DLTs were due to inhibition of JAK‐1/2 or to off‐target effects is unknown. The unusual DLTs and the lack of clinical activity led to discontinuation of development. Abstract : 摘要 背景 . AZD1480是抑制Janus相关激酶‐1和‐2（JAK1和JAK2）的新型药物。本项I期研究的主要目的是调查AZD1480单药治疗实体瘤患者的安全性和耐受性。 方法 : 共38例晚期癌症患者接受AZD1480治疗，剂量为10 ∼ 70mg每日1次（QD）或20 ∼ 45mg每日2次（BID）。 结果 . 药代动力学（PK）分析显示AZD1480QD或BID重复给药后迅速吸收和排泄，仅有极少在体内累积。10 ∼ 50 mg剂量之间的药物暴露水平增加呈剂量依赖性。给药约1h后达到血浆峰浓度（Cmax ），而半衰期（t1/2 ）约为5h。循环粒细胞的药效学分析证实AZD1480给药后1 ∼ 2 h对磷酸化STAT3（pSTAT3）的抑制效应最强，与Cmax 出现时间一致，且剂量越高pSTAT3抑制效应越强。给药剂量最大（即70 mg QD）时，稳态药物浓度下粒细胞pSTAT3的平均抑制程度为56%（标准差：±21%）。剂量限制性毒性（DLT）包括多种表现的神经系统不良事件（AE），如头晕、焦虑、共济失调、失忆、幻觉和行为改变。随着剂量减小或治疗中止，这些AE通常可逆。 结论 .DLT究竟是由JAK‐1/2抑制还是脱靶效应引起仍未可知。非常规的DLT事件和临床疗效不足导致了药物研发的中止。