Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
Cancer. 2019 Feb 15;125(4):533-540. doi: 10.1002/cncr.31817. Epub 2018 Dec 20.
The authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in CREB binding protein [CREBBP] and/or E1A binding protein p300 [EP300] histone acetyltransferase genes in a single-arm, open-label phase 2 study.
Eligible patients with platinum-treated, advanced/metastatic disease received oral mocetinostat (at a dose of 70 mg 3 times per week [TIW] escalating to 90 mg TIW) in 28-day cycles in a 3-stage study (ClinicalTrials.gov identifier NCT02236195). The primary endpoint was the objective response rate.
Genomic testing was feasible in 155 of 175 patients (89%). Qualifying tumor mutations were CREBBP (15%), EP300 (8%), and both CREBBP and EP300 (1%). A total of 17 patients were enrolled into stage 1 (the intent-to-treat population); no patients were enrolled in subsequent stages. One partial response was observed (11% [1 of 9 patients; the population that was evaluable for efficacy comprised 9 of the 15 planned patients]); activity was deemed insufficient to progress to stage 2 (null hypothesis: objective response rate of ≤15%). All patients experienced ≥1 adverse event, most commonly nausea (13 of 17 patients; 77%) and fatigue (12 of 17 patients; 71%). The median duration of treatment was 46 days; treatment interruptions (14 of 17 patients; 82%) and dose reductions (5 of 17 patients; 29%) were common. Mocetinostat exposure was lower than anticipated (dose-normalized maximum serum concentration [C ] after TIW dosing of 0.2 ng/mL/mg).
To the authors' knowledge, the current study represents the first clinical trial using genomic-based selection to identify patients with urothelial cancer who are likely to benefit from selective histone deacetylase inhibition. Mocetinostat was associated with significant toxicities that impacted drug exposure and may have contributed to modest clinical activity in these pretreated patients. The efficacy observed was considered insufficient to warrant further investigation of mocetinostat as a single agent in this setting.
作者在一项单臂、开放标签的 2 期研究中评估了莫塞替尼（一种 I/IV 类组蛋白去乙酰化酶抑制剂）在携带 CREB 结合蛋白[CREBBP]和/或 E1A 结合蛋白 p300[EP300]组蛋白乙酰转移酶基因失活突变或缺失的尿路上皮癌患者中的疗效。
符合条件的铂类治疗后，晚期/转移性疾病患者接受口服莫塞替尼（剂量为 70mg，每周 3 次[TIW]，递增至 90mg TIW），每 28 天为一个周期，分为 3 个阶段进行研究（ClinicalTrials.gov 标识符 NCT02236195）。主要终点是客观缓解率。
在 175 名患者中有 155 名（89%）可进行基因组检测。合格的肿瘤突变是 CREBBP（15%）、EP300（8%）和 CREBBP 和 EP300 均有突变（1%）。共招募了 17 名患者进入第 1 阶段（意向治疗人群）；没有患者进入后续阶段。观察到 1 例部分缓解（9 名可评估疗效的患者中 1 例；客观缓解率为 11%[9 名计划患者中的 1 名]）；活性不足以进入第 2 阶段（零假设：客观缓解率≤15%）。所有患者均经历了≥1 次不良反应，最常见的是恶心（17 名患者中有 13 名；77%）和疲劳（17 名患者中有 12 名；71%）。中位治疗时间为 46 天；治疗中断（17 名患者中有 14 名；82%）和剂量减少（17 名患者中有 5 名；29%）很常见。莫塞替尼的暴露量低于预期（每周 3 次 TIW 给药后的剂量标准化最大血清浓度[C]为 0.2ng/ml/mg）。
据作者所知，目前的研究代表了首次使用基于基因组的选择来识别可能从选择性组蛋白去乙酰化酶抑制中获益的尿路上皮癌患者的临床试验。莫塞替尼与显著的毒性相关，影响药物暴露，并可能导致这些预处理患者的临床活性适度。观察到的疗效被认为不足以证明莫塞替尼作为单一药物在该环境中进一步研究是合理的。
