Division of Oncology, Washington University School of Medicine, St Louis, MO, USA.
Jewish General Hospital, Montreal, QC, Canada.
Invest New Drugs. 2020 Oct;38(5):1430-1441. doi: 10.1007/s10637-020-00907-4. Epub 2020 Feb 4.
In acute myeloid leukemia (AML), TP53 mutations and dysregulation of wild-type p53 is common and supports an MDM2 antagonist as a therapy. RO6839921 is an inactive pegylated prodrug of the oral MDM2 antagonist idasanutlin (active principle [AP]) that allows for IV administration. This phase 1 monotherapy study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with AML. Primary objectives identified dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Secondary objectives assessed pharmacokinetic, pharmacodynamic, and antileukemic activity. A total of 26 patients received 120-300 mg AP of idasanutlin. The MTD was 200 mg, with DLTs at 250 (2/8 patients) and 300 mg (2/5). Treatment-related adverse events in >20% of patients were diarrhea, nausea, vomiting, decreased appetite, and fatigue. Six deaths (23.1%) occurred, all unrelated to treatment. Pharmacokinetics showed rapid and near-complete conversion of the prodrug to AP and dose-proportional exposure across doses. Variability ranged from 30%-47% (22%-54% for idasanutlin). TP53 was 21 (87.5%) wild-type and 3 mutant (12.5%). The composite response rate (complete remission [CR], CR with incomplete hematologic recovery/morphological leukemia-free state [CRi/MLFS], or CR without platelet recovery [CRp]) was 7.7%. Antileukemic activity (CR, CRi/MLFS, partial response, hematologic improvement/stable disease) was observed in 11 patients (disease control rate, 42%): 10/11 were TP53 wild-type; 1 had no sample. p53 activation was demonstrated by MIC-1 induction and was associated with AP exposure. There was not sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development of RO6839921. NCT02098967.
在急性髓细胞白血病（AML）中，TP53 突变和野生型 p53 的失调很常见，支持将 MDM2 拮抗剂作为一种治疗方法。RO6839921 是一种口服 MDM2 拮抗剂 idasanutlin 的无活性聚乙二醇化前药（有效成分 [AP]），可进行 IV 给药。这项单药治疗的 1 期研究评估了 RO6839921 在 AML 患者中的安全性、药代动力学和药效学。主要目标确定剂量限制性毒性（DLT）和最大耐受剂量（MTD）。次要目标评估药代动力学、药效学和抗白血病活性。共有 26 名患者接受了 120-300mgAP 的 idasanutlin 治疗。MTD 为 200mg，250mg（8 名患者中的 2 名）和 300mg（5 名患者中的 2 名）有 DLT。>20%的患者出现与治疗相关的不良反应为腹泻、恶心、呕吐、食欲下降和疲劳。6 例死亡（23.1%）与治疗无关。药代动力学显示前药快速且几乎完全转化为 AP，且剂量与暴露呈比例。变异性范围为 30%-47%（伊沙那肽为 22%-54%）。TP53 有 21 个（87.5%）为野生型，3 个为突变型（12.5%）。复合缓解率（完全缓解 [CR]、不完全血液学恢复/形态学白血病无状态 [CRi/MLFS]或无血小板恢复的 CR [CRp]）为 7.7%。11 名患者观察到抗白血病活性（CR、CRi/MLFS、部分缓解、血液学改善/稳定疾病）（疾病控制率为 42%）：10/11 为 TP53 野生型；1 名患者无样本。通过 MIC-1 诱导证明了 p53 激活，并与 AP 暴露相关。与口服伊沙那肽相比，其在生物学或安全性方面没有足够的差异或改善，因此不支持继续开发 RO6839921。NCT02098967。
