A Phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of CXD101 in patients with advanced solid-organ cancer expressing HR23B or lymphoma.
A Phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of CXD101 in patients with advanced solid-organ cancer expressing HR23B or lymphoma.
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DOI：
10.1186/s12885-021-08595-w
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发表时间：
2021-07-23
期刊：
影响因子：
3.8
通讯作者：
Collins GP
中科院分区：
文献类型：
--
作者：
Booth SW;Eyre TA;Whittaker J;Campo L;Wang LM;Soilleux E;Royston D;Rees G;Kesavan M;Hildyard C;Kazmi F;La Thangue N;Kerr D;Middleton MR;Collins GP
这项2a期剂量扩大研究旨在评估口服组蛋白去乙酰化酶（HDAC）抑制剂CXD101在复发/难治性淋巴瘤或晚期实体器官癌患者中最大耐受剂量的安全性、耐受性和初步疗效，并通过免疫组织化学评估HR23B蛋白表达作为HDAC抑制剂敏感性的生物标志物。HR23B高表达的晚期实体器官癌或淋巴瘤患者接受推荐的2期剂量（RP2D）的CXD101治疗。关键排除：校正后的QT > 450 ms，中性粒细胞< 1.5 × 109/L，血小板< 75 × 109/L, ECOG > 1。免疫组织化学检测HR23B基线表达。在2014年3月至2019年9月期间入组的51例患者中，47例接受了CXD101治疗（19例实体器官癌，28例淋巴瘤）。34例患者的RP2D≥80%。基线特征：中位年龄57.4岁，中位既往行数3条，男性57%。最常见的3-4级不良事件是中性粒细胞减少症（32%）、血小板减少症（17%）、贫血（13%）和疲劳（9%），使用CXD101无死亡病例。实体器官癌未见应答，36%的患者病情稳定；淋巴瘤的总缓解率为17%，52%的患者病情稳定。实体器官癌的中位无进展生存期为1.2个月（95%可信区间（CI） 1.2 - 5.4），淋巴瘤的中位无进展生存期为2.6个月（95%CI 1.2 - 5.6）。HR23B状态不能预测反应。CXD101在霍奇金淋巴瘤、t细胞淋巴瘤和滤泡性淋巴瘤中表现出可接受的耐受性和疗效。评估联合方法的进一步研究是必要的。ClinicalTrials.gov识别码NCT01977638。注册于2013年11月7日。在线版本包含补充材料，可在10.1186/s12885-021-08595-w获得。
This Phase 2a dose expansion study was performed to assess the safety, tolerability and preliminary efficacy of the maximum tolerated dose of the oral histone de-acetylase (HDAC) inhibitor CXD101 in patients with relapsed / refractory lymphoma or advanced solid organ cancers and to assess HR23B protein expression by immunohistochemistry as a biomarker of HDAC inhibitor sensitivity. Patients with advanced solid-organ cancers with high HR23B expression or lymphomas received CXD101 at the recommended phase 2 dose (RP2D). Key exclusions: corrected QT > 450 ms, neutrophils < 1.5 × 109/L, platelets < 75 × 109/L, ECOG > 1. Baseline HR23B expression was assessed by immunohistochemistry. Fifty-one patients enrolled between March 2014 and September 2019, 47 received CXD101 (19 solid-organ cancer, 28 lymphoma). Thirty-four patients received ≥80% RP2D. Baseline characteristics: median age 57.4 years, median prior lines 3, male sex 57%. The most common grade 3–4 adverse events were neutropenia (32%), thrombocytopenia (17%), anaemia (13%), and fatigue (9%) with no deaths on CXD101. No responses were seen in solid-organ cancers, with disease stabilisation in 36% or patients; the overall response rate in lymphoma was 17% with disease stabilisation in 52% of patients. Median progression-free survival was 1.2 months (95% confidence interval (CI) 1.2–5.4) in solid-organ cancers and 2.6 months (95%CI 1.2–5.6) in lymphomas. HR23B status did not predict response. CXD101 showed acceptable tolerability with efficacy seen in Hodgkin lymphoma, T-cell lymphoma and follicular lymphoma. Further studies assessing combination approaches are warranted. ClinicalTrials.gov identifier NCT01977638. Registered 07 November 2013. The online version contains supplementary material available at 10.1186/s12885-021-08595-w.
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