Phase I trial of histone deacetylase inhibition by valproic acid followed by the topoisomerase II inhibitor epirubicin in advanced solid tumors:: A clinical and translational study
Phase I trial of histone deacetylase inhibition by valproic acid followed by the topoisomerase II inhibitor epirubicin in advanced solid tumors:: A clinical and translational study
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DOI：
10.1200/jco.2006.08.6165
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发表时间：
2007-05-20
影响因子：
45.3
通讯作者：
Daud, Adil
中科院分区：
文献类型：
--
作者：
Muenster, Pamela;Marchion, Douglas;Daud, Adil
PurposeTo确定组蛋白去乙酰化酶抑制剂（HDACi），丙戊酸（VPA），和表阿霉素在实体瘤恶性肿瘤的序列特异性组合的安全性，毒性和最大耐受剂量，并定义VPA作为HDACi.Patients和MethodsPatients的临床可行性进行治疗与增加剂量的VPA（第1至3天），然后表阿霉素（第3天）在3周的周期。这项研究评估了药代动力学和药效学终点，毒性，和肿瘤responsibility. ResultsForeignPatients入组，44个接受至少一个周期的治疗。患者（中位年龄54岁;范围39 - 78岁）接受以下剂量的VPA：15、30、45、60、75、90、100、120、140和160 mg/kg/d。剂量限制性毒性为嗜睡（n = 1）、意识模糊（n = 3）和发热性中性粒细胞减少症（n = 1）。未观察到表柔比星相关毒性加重。在9例患者（22%）中观察到不同肿瘤类型的部分缓解，在16例患者（39%）中观察到稳定的疾病/轻微缓解，尽管中位数为3种既往治疗方案（范围为0至10种既往治疗方案）。患者接受了中位4个治疗周期（范围1 - 10个周期），41例患者中有13例（32%）在达到最大表阿霉素剂量后停止治疗，而不是进展。总的和游离的VPA血浆浓度随剂量线性增加，并与组蛋白乙酰化在外周血mononuclearcells.ConclusionThe最大耐受剂量和推荐的第二阶段剂量为VPA 140 mg/kg/d，48小时，随后epiravirus 100 mg/m2。VPA的持续血浆浓度超过体外协同作用所需的浓度，毒性可接受。值得注意的抗肿瘤活性中观察到大量预处理的患者和历史上蒽环类药物耐药的肿瘤。
PurposeTo determine the safety, toxicity, and maximum-tolerated dose of a sequence-specific combination of the histone deacetylase inhibitor (HDACi), valproic acid (VPA), and epirubicin in solid tumor malignancies and to define the clinical feasibility of VPA as an HDACi.Patients and MethodsPatients were treated with increasing doses of VPA (days 1 through 3) followed by epirubicin (day 3) in 3-week cycles. The study evaluated pharmacokinetic and pharmacodynamic end points, toxicities, and tumor response.ResultsForty-eight patients were enrolled, and 44 received at least one cycle of therapy. Patients (median age, 54 years; range, 39 to 78 years) received the following doses of VPA: 15, 30, 45, 60, 75, 90, 100, 120, 140, and 160 mg/kg/d. Dose-limiting toxicities were somnolence (n = 1), confusion (n = 3), and febrile neutropenia (n = 1). No exacerbation of epirubicin-related toxicities was observed. Partial responses were seen across different tumor types in nine patients (22%), and stable disease/minor responses were seen in 16 patients (39%), despite a median number of three prior regimens (range, zero to 10 prior regimens). Patients received a median number of four treatment cycles (range, one to 10 cycles), and treatment was stopped after reaching maximal epirubicin doses rather than progression in 13 (32%) of 41 patients patients. Total and free VPA plasma concentrations increased linearly with dose and correlated with histone acetylation in peripheral-blood mononuclear cells.ConclusionThe maximum-tolerated dose and recommended phase II dose was VPA 140 mg/kg/d for 48 hours followed by epirubicin 100 mg/m(2). Sustained plasma concentrations of VPA exceeding those required for in vitro synergy were achieved with acceptable toxicity. Noteworthy antitumor activity was observed in heavily pretreated patients and historically anthracycline-resistant tumors.