背景:Citarinostat(CC-96241;以前为ACY-241),一种对HDAC6具有选择性的组蛋白脱乙酰酶(HDACs)口服抑制剂,在多种实体瘤模型中已证明与紫杉醇具有协同抗癌活性.在本Ib3+3期剂量递增研究中,对晚期实体瘤患者进行了使用西达诺他与紫杉醇的联合治疗。
方法:先前治疗过的晚期实体瘤患者在第1天至第21天每天一次接受西达诺他180、360或480mg,并在第1、8和15天接受紫杉醇80mg/m2的治疗,直至疾病进展或不可接受的毒性。主要终点是确定最大耐受剂量(MTD)。次要终点包括安全性,抗肿瘤活性,药代动力学,和药效学。
结果:20例患者入选并接受研究治疗;15例患者之前接受过紫杉烷治疗。没有报告任何剂量的剂量限制性毒性;因此,MTD没有确定。Citarinostat360与480mg与中性粒细胞减少的发生率和严重程度相关。3名患者经历了确认的部分反应,13名患者病情稳定。药代动力学参数呈线性关系,直至西他司他360mg,在外周血单核细胞中观察到组蛋白和微管蛋白乙酰化水平最高的剂量。
结论:西达诺他与紫杉醇的联合用药显示出可接受的安全性,在严重预处理的晚期实体瘤患者中,没有意外或剂量限制性毒性和抗肿瘤活性的潜在证据。Citarinostat每天一次360mg被认为是与紫杉醇80mg/m2联合使用的推荐II期剂量,每3/4周。该试验在ClinicalTrials.gov(NCT02551185)上注册。
BACKGROUND: Citarinostat (CC-96241; previously ACY-241), an oral inhibitor of histone deacetylases (HDACs) with selectivity for HDAC6, has demonstrated synergistic anticancer activity with paclitaxel in multiple solid tumor models. Combination therapy using citarinostat with paclitaxel was evaluated in this phase Ib 3 + 3 dose-escalation
study in patients with advanced solid tumors.
METHODS: Patients with previously treated advanced solid tumors received citarinostat 180, 360, or 480 mg once daily on days 1 to 21 plus paclitaxel 80 mg/m2 on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was determination of the maximum tolerated dose (MTD). Secondary endpoints included safety, antitumor activity, pharmacokinetics, and pharmacodynamics.
RESULTS: Twenty patients were enrolled and received
study treatment; 15 had received prior taxane therapy. No dose-limiting toxicities were reported at any dose; therefore, the MTD was not identified. Citarinostat 360 vs 480 mg was associated with reduced incidence and severity of neutropenia. Three patients experienced a confirmed partial response and 13 achieved stable disease. Pharmacokinetic parameters were linear up to citarinostat 360 mg, the dose at which the highest levels of histone and tubulin acetylation were observed in peripheral blood mononuclear cells.
CONCLUSIONS: The combination of citarinostat plus paclitaxel showed an acceptable safety profile, with no unexpected or dose-limiting toxicities and potential evidence of antitumor activity in patients with heavily pretreated advanced solid tumors. Citarinostat 360 mg once daily is considered the recommended phase II dose for use in combination with paclitaxel 80 mg/m2 every 3 of 4 weeks. This
trial is registered on ClinicalTrials.gov (NCT02551185).