A phase I/II trial of belinostat in combination with cisplatin, doxorubicin, and cyclophosphamide in thymic epithelial tumors: a clinical and translational study.
A phase I/II trial of belinostat in combination with cisplatin, doxorubicin, and cyclophosphamide in thymic epithelial tumors: a clinical and translational study.
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DOI：
10.1158/1078-0432.ccr-14-0968
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发表时间：
2014-11-01
期刊：
影响因子：
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通讯作者：
Giaccone G
中科院分区：
文献类型：
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作者：
Thomas A;Rajan A;Szabo E;Tomita Y;Carter CA;Scepura B;Lopez-Chavez A;Lee MJ;Redon CE;Frosch A;Peer CJ;Chen Y;Piekarz R;Steinberg SM;Trepel JB;Figg WD;Schrump DS;Giaccone G
这项 I/II 期研究旨在确定贝利司他新方案的安全性和最大耐受剂量 (MTD)，贝利司他是一种组蛋白脱乙酰酶抑制剂，在胸腺上皮肿瘤 (TET) 中先于顺铂 (P)、阿霉素 (A) 和环磷酰胺 (C) 给药，并与顺铂 (P)、阿霉素 (A) 和环磷酰胺 (C) 联用。还评估了抗肿瘤活性、药代动力学和反应生物标志物。晚期不可切除的 TET 患者接受增加剂量的贝利司他连续静脉输注超过 48 小时，并以 3 周为周期进行化疗。在 II 期中，使用了 MTD 的贝利司他。入组了 26 名患者（胸腺瘤：12 例；胸腺癌：14 例）。两名患者在 2000 mg/m2 贝利司他剂量下的剂量限制性毒性分别为 3 级恶心和腹泻以及 4 级中性粒细胞减少和血小板减少。 24 名患者以 1000 mg/m2 的 MTD 接受化疗（第 2 天 P 50 mg/m2；第 2、3 天 A 25 mg/m2；第 3 天 C 500 mg/m2）。胸腺瘤和胸腺癌的客观缓解率分别为 64% [95% 置信区间：30.8%–89.1%] 和 21% (4.7%–50.8%)。观察到 HDAC 抑制的药效学标志物的调节以及调节性 T 细胞 (Treg) 和耗尽的 CD8+ T 细胞群的下降。 Tregs 的下降与缓解 (p=0.0041) 和无进展生存期 (p=0.021) 相关。应答者中 TIM-3+ CD8+T 细胞的下降幅度大于无应答者 (p=0.049)。本研究确定了贝利司他与 PAC 组合的 MTD，并表明该组合在 TET 中是有效且可行的。对调节性 T 细胞和 TIM3+ CD8+ T 细胞的免疫调节作用值得进一步研究。
This phase I/II study sought to determine the safety and maximum-tolerated dose (MTD) of a novel schedule of belinostat, a histone deacetylase inhibitor administered prior to and in combination with cisplatin (P), doxorubicin (A) and cyclophosphamide (C) in thymic epithelial tumors (TET). Anti-tumor activity, pharmacokinetics, and biomarkers of response were also assessed. Patients with advanced, unresectable TET received increasing doses of belinostat as a continuous intravenous infusion over 48-hours with chemotherapy in 3-week cycles. In phase II, belinostat at the MTD was used. 26 patients were enrolled (thymoma: 12; thymic carcinoma: 14). Dose-limiting toxicities at 2000 mg/m2 belinostat were grade 3 nausea and diarrhea and grade 4 neutropenia and thrombocytopenia, respectively, in two patients. 24 patients were treated at the MTD of 1000 mg/m2 with chemotherapy (P 50 mg/m2 on day 2; A 25 mg/m2 on days 2, 3; C 500 mg/m2 on day 3). Objective response rates in thymoma and thymic carcinoma were 64% [95% confidence interval: 30.8%–89.1%] and 21% (4.7%–50.8%) respectively. Modulation of pharmacodynamic markers of HDAC-inhibition and declines in regulatory T cell (Tregs) and exhausted CD8+ T cell populations were observed. Decline in Tregs was associated with response (p=0.0041) and progression-free survival (p=0.021). Declines in TIM-3+ CD8+T cells were larger in responders than non-responders (p=0.049). This study identified the MTD of belinostat in combination with PAC and indicates that the combination is active and feasible in TETs. Immunomodulatory effects on regulatory T cells and TIM3+ CD8+ T cells warrant further study.