Medical Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland 20892, USA.
Clin Cancer Res. 2013 Aug 15;19(16):4499-507. doi: 10.1158/1078-0432.CCR-13-0095. Epub 2013 Jun 11.
Romidepsin is a potent histone deacetylase inhibitor (HDI) with activity in T-cell lymphoma. Given preclinical data showing greater induction of gene expression with longer exposures to HDIs, a phase I study of a day 1, 3, and 5 romidepsin schedule was evaluated. A secondary objective was to assess the effect of romidepsin on radioactive iodine (RAI) uptake in thyroid cancers.
Open-label, single-arm, phase I, 3 + 3 dose escalation study. Romidepsin was administered as a 4-hour infusion on days 1, 3, and 5 of a 21-day cycle. Pharmacokinetics (PK) and pharmacodynamics (PD) were assessed, including histone acetylation in peripheral blood mononuclear cells (PBMC), RAI uptake in refractory thyroid cancer, and HDI-related ECG changes.
Twenty-eight patients with solid tumors, including 11 patients with thyroid cancer were enrolled. Six dose levels were explored, and 7 mg/m(2) on days 1, 3, and 5 was identified as tolerable. No Response Evaluation Criteria In Solid Tumors-defined objective responses were recorded although 9 patients had stable disease a median 30 weeks (range, 21-112) including 6 with thyroid cancer a median of 33 weeks. PD studies detected acetylated histones in PBMCs and ECG changes beginning at low dose levels. Follow-up RAI scans in patients with RAI refractory thyroid cancer did not detect meaningful increases.
A romidepsin dose of 7 mg/m(2) administered on days 1, 3, and 5 was found tolerable and resulted in histone acetylation in PBMCs. Although there were no objective responses with romidepsin alone, this schedule may be useful for developing combination studies in solid tumors.
罗米地辛是一种有效的组蛋白去乙酰化酶抑制剂（HDACi），在 T 细胞淋巴瘤中具有活性。鉴于临床前数据显示，HDACi 暴露时间越长，基因表达的诱导作用越大，因此评估了罗米地辛 1 天、3 天和 5 天方案的 I 期研究。次要目标是评估罗米地辛对甲状腺癌放射性碘（RAI）摄取的影响。
开放标签、单臂、I 期、3+3 剂量递增研究。罗米地辛在 21 天周期的第 1、3 和 5 天给予 4 小时输注。评估了药代动力学（PK）和药效学（PD），包括外周血单核细胞（PBMC）中的组蛋白乙酰化、难治性甲状腺癌中的 RAI 摄取以及与 HDACi 相关的心电图变化。
共纳入 28 例实体瘤患者，包括 11 例甲状腺癌患者。探索了 6 个剂量水平，确定 1、3 和 5 天的 7mg/m²剂量是可耐受的。尽管有 9 例患者疾病稳定（中位时间 30 周，范围 21-112 周），包括 6 例甲状腺癌患者（中位时间 33 周），但未记录到根据实体瘤反应评估标准定义的客观反应。PD 研究在低剂量水平时检测到 PBMC 中的乙酰化组蛋白和心电图变化。对 RAI 难治性甲状腺癌患者的后续 RAI 扫描未检测到有意义的增加。
在 1、3 和 5 天给予 7mg/m²的罗米地辛是可耐受的，导致 PBMC 中的组蛋白乙酰化。虽然单独使用罗米地辛没有客观反应，但该方案可能对开发实体瘤联合研究有用。
