A phase I trial of panobinostat and epirubicin in solid tumors with a dose expansion in patients with sarcoma.
A phase I trial of panobinostat and epirubicin in solid tumors with a dose expansion in patients with sarcoma.
复制标题
帕比司他和表柔比星治疗实体瘤的 I 期试验，并扩大了肉瘤患者的剂量。
DOI：
10.1093/annonc/mdw044
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Munster,PN
中科院分区：
文献类型：
--
作者：
Thomas,S;Aggarwal,R;Jahan,T;Ryan,C;Troung,T;Cripps,AM;Raha,P;Thurn,KT;Chen,S;Grabowsky,JA;Park,J;Hwang,J;Daud,A;Munster,PN
BackgroundTreatment options for sarcoma are limited. Histone deacetylase inhibitors increase the efficacy of topoisomerase II inhibitors by promoting access to chromatin and by down-regulating DNA repair. Thus, combined panobinostat and epirubicin therapy was evaluated to treat refractory sarcoma.Patients and methodsPatients with advanced solid tumors were enrolled in a 3 + 3 dose-escalation phase I trial of panobinostat given on days 1, 3, and 5 followed by 75 mg/m2of epirubicin on day 5 in 21-day cycles, with a dose expansion at maximum tolerated dose (MTD) in 20 sarcoma patients. Peripheral blood mononucleocyte histone acetylation was also evaluated.ResultsForty patients received 20–60 mg panobinostat. Dose-limiting toxicities included thrombocytopenia, febrile neutropenia, and fatigue at 60 mg, defining a panobinostat MTD at 50 mg. Four responses were seen in 37 assessable patients, all after progression on prior topoisomerase II inhibitors. For those with sarcoma, 12 of 20 derived clinical benefit (1 partial response and 11 stable disease, median overall survival 8.3 months), including 8 of 14 previously progressed on topoisomerase II therapy. Treatment benefits correlated with increased histone acetylation and decreased neutrophil count on day 5.ConclusionsPanobinostat and epirubicin treatment is well tolerated and may reverse anthracycline resistance. Changes in histone acetylation and associated decrease in neutrophil count correlated with clinical benefit and warrant investigation as predictive biomarkers.Clinical trialThis trial is registered at www.Clinicaltrials.gov, Identifier: NCT00878904.
