A phase I study of the safety and pharmacokinetics of the histone deacetylase inhibitor belinostat administered in combination with carboplatin and/or paclitaxel in patients with solid tumours.
A phase I study of the safety and pharmacokinetics of the histone deacetylase inhibitor belinostat administered in combination with carboplatin and/or paclitaxel in patients with solid tumours.
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DOI：
10.1038/sj.bjc.6605726
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发表时间：
2010-06-29
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
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作者：
这项 I 期研究评估了贝利司他与卡铂和紫杉醇的最大耐受剂量、剂量限制毒性 (DLT) 和药代动力学，以及该组合在实体瘤中的抗肿瘤活性。 3 至 6 名患者组成的队列接受递增剂量的贝利司他静脉注射，每天一次，第 1-5 天，每 21 天一次；第3天，贝利司他输注结束后2-3小时给予卡铂（曲线下面积（AUC）5）和/或紫杉醇（175mgm−2）。所有 23 名患者每天接受 600–1000mgm−2 的贝利司他联合卡铂和/或紫杉醇治疗。没有观察到 DLT。贝利司他的最大给药剂量为每天 1000mg m−2，持续第 1-5 天，第 3 天给予紫杉醇 (175mg m−2) 和卡铂 AUC 5。 III/IV 级不良事件为 (n; %)：白细胞减少症 (5; 22%)、中性粒细胞减少症 (7; 30%)、血小板减少症(3; 13%) 贫血 (1; 4%)、周围感觉神经病变 (2; 9%)、疲劳 (1; 4%)、呕吐 (1; 4%) 和肌痛 (1; 4%)。贝利司他、紫杉醇和卡铂的药代动力学未因同时给药而改变。有两种部分缓解（一种直肠癌和一种胰腺癌）。第三名患者（卵巢起源的混合苗勒管肿瘤）显示出完全的 CA-125 反应。此外，六名患者的疾病稳定持续⩾6个月。该组合具有良好的耐受性，没有证据表明存在药代动力学相互作用。有必要进一步评估抗肿瘤活性。
This phase I study assessed the maximum tolerated dose, dose-limiting toxicity (DLT) and pharmacokinetics of belinostat with carboplatin and paclitaxel and the anti-tumour activity of the combination in solid tumours. Cohorts of three to six patients were treated with escalating doses of belinostat administered intravenously once daily, days 1–5 q21 days; on day 3, carboplatin (area under the curve (AUC) 5) and/or paclitaxel (175 mg m−2) were administered 2–3 h after the end of the belinostat infusion. In all 23 patients received 600–1000 mg m−2 per day of belinostat with carboplatin and/or paclitaxel. No DLT was observed. The maximal administered dose of belinostat was 1000 mg m−2 per day for days 1–5, with paclitaxel (175 mg m−2) and carboplatin AUC 5 administered on day 3. Grade III/IV adverse events were (n; %): leucopenia (5; 22%), neutropenia (7; 30%), thrombocytopenia (3; 13%) anaemia (1; 4%), peripheral sensory neuropathy (2; 9%), fatigue (1; 4%), vomiting (1; 4%) and myalgia (1; 4%). The pharmacokinetics of belinostat, paclitaxel and carboplatin were unaltered by the concurrent administration. There were two partial responses (one rectal cancer and one pancreatic cancer). A third patient (mixed mullerian tumour of ovarian origin) showed a complete CA-125 response. In addition, six patients showed a stable disease lasting ⩾6 months. The combination was well tolerated, with no evidence of pharmacokinetic interaction. Further evaluation of anti-tumour activity is warranted.
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影响因子：
45.3
作者：
Muenster, Pamela;Marchion, Douglas;Daud, Adil
通讯作者：
Daud, Adil
影响因子：
5.7
作者：
Marchion, DC;Bicaku, E;Munster, PN
通讯作者：
Munster, PN
影响因子：
11.5
作者：
Piekarz, Richard L.;Frye, A. Robin;Bates, Susan E.
通讯作者：
Bates, Susan E.
影响因子：
11.5
作者：
Steele, Nicola L.;Plumb, Jane A.;DeBono, Johann S.
通讯作者：
DeBono, Johann S.
DOI：
10.1093/jnci/92.3.205
发表时间：
2000-02-02
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Therasse, P;Arbuck, SG;Gwyther, SG
通讯作者：
Gwyther, SG