BACKGROUND Until today, adult and pediatric clinical trials investigating single-agent or combinatorial HDAC inhibitors including vorinostat in solid tumors have largely failed to demonstrate efficacy. These results may in part be explained by data from preclinical models showing significant activity only at higher concentrations compared to those achieved with current dosing regimens. In the current pediatric trial, we applied an intra-patient dose escalation design. The purpose of this trial was to determine a safe dose recommendation (SDR) of single-agent vorinostat for intra-patient dose escalation, pharmacokinetic analyses (PK), and activity evaluation in children (3-18 years) with relapsed or therapy-refractory malignancies. RESULTS A phase I intra-patient dose (de)escalation was performed until individual maximum tolerated dose (MTD). The starting dose was 180 mg/m2/day with weekly dose escalations of 50 mg/m2 until DLT/maximum dose. After MTD determination, patients seamlessly continued in phase II with disease assessments every 3 months. PK and plasma cytokine profiles were determined. Fifty of 52 patients received treatment. n = 27/50 (54%) completed the intra-patient (de)escalation and entered phase II. An SDR of 130 mg/m2/day was determined (maximum, 580 mg/m2/day). n = 46/50 (92%) patients experienced treatment-related AEs which were mostly reversible and included thrombocytopenia, fatigue, nausea, diarrhea, anemia, and vomiting. n = 6/50 (12%) had treatment-related SAEs. No treatment-related deaths occurred. Higher dose levels resulted in higher Cmax. Five patients achieved prolonged disease control (> 12 months) and showed a higher Cmax (> 270 ng/mL) and MTDs. Best overall response (combining PR and SD, no CR observed) rate in phase II was 6/27 (22%) with a median PFS and OS of 5.3 and 22.4 months. Low levels of baseline cytokine expression were significantly correlated with favorable outcome. CONCLUSION An SDR of 130 mg/m2/day for individual dose escalation was determined. Higher drug exposure was associated with responses and long-term disease stabilization with manageable toxicity. Patients with low expression of plasma cytokine levels at baseline were able to tolerate higher doses of vorinostat and benefited from treatment. Baseline cytokine profile is a promising potential predictive biomarker. TRIAL REGISTRATION ClinicalTrials.gov, NCT01422499. Registered 24 August 2011.

中文翻译：

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伏立诺他I / II期患者体内剂量递增研究对复发性实体瘤，淋巴瘤或白血病患儿的研究。

背景技术直到今天，在实体瘤中研究包括伏立诺他在内的单药或组合HDAC抑制剂的成人和儿科临床试验在很大程度上仍未显示出疗效。这些结果可能部分由临床前模型的数据解释，这些数据显示，与当前给药方案相比，仅在更高的浓度下才具有明显的活性。在当前的儿科试验中，我们应用了患者内剂量递增设计。该试验的目的是确定单药伏立诺他的安全剂量推荐（SDR），用于复发或治疗难治的儿童（3至18岁）的患者内剂量递增，药代动力学分析（PK）和活动评估恶性肿瘤。结果进行了I期患者的剂量（降）升高，直到个体的最大耐受剂量（MTD）为止。起始剂量为180 mg / m2 /天，每周剂量递增50 mg / m2，直到DLT /最大剂量。确定MTD后，患者每3个月无缝进入II期疾病评估。确定了PK和血浆细胞因子谱。52名患者中有50名接受了治疗。n = 27/50（54％）完成了患者内（去）递增并进入II期。确定的SDR为130毫克/平方米/天（最大580毫克/平方米/天）。n = 46/50（92％）患者经历了与治疗相关的AE，大多数可逆，包括血小板减少症，疲劳，恶心，腹泻，贫血和呕吐。n = 6/50（12％）患有与治疗相关的SAE。没有发生与治疗有关的死亡。较高的剂量水平导致较高的Cmax。五名患者获得了更长的疾病控制时间（> 12个月），并显示出更高的Cmax（> 270 ng / mL）和MTD。第二阶段的最佳总体缓解率（结合PR和SD，未观察到CR）的发生率为6/27（22％），中位PFS和OS分别为5.3和22.4个月。基线细胞因子表达水平低与预后良好相关。结论确定个体剂量递增的SDR为130 mg / m2 /天。较高的药物暴露量与反应和使疾病长期稳定并具有可控毒性有关。基线时血浆细胞因子水平低表达的患者能够耐受较高剂量的伏立诺他，并从治疗中受益。基线细胞因子谱是有前途的潜在预测生物标志物。试验注册ClinicalTrials.gov，NCT01422499。2011年8月24日注册。3和22.4个月。基线细胞因子表达水平低与预后良好相关。结论确定个体剂量递增的SDR为130 mg / m2 /天。较高的药物暴露量与反应和使疾病长期稳定并具有可控毒性有关。基线时血浆细胞因子水平低表达的患者能够耐受较高剂量的伏立诺他，并从治疗中受益。基线细胞因子谱是有前途的潜在预测生物标志物。试验注册ClinicalTrials.gov，NCT01422499。2011年8月24日注册。3和22.4个月。基线细胞因子表达水平低与预后良好相关。结论确定个体剂量递增的SDR为130 mg / m2 /天。较高的药物暴露量与反应和使疾病长期稳定并具有可控毒性有关。基线时血浆细胞因子水平低表达的患者能够耐受较高剂量的伏立诺他，并从治疗中受益。基线细胞因子谱是有前途的潜在预测生物标志物。试验注册ClinicalTrials.gov，NCT01422499。2011年8月24日注册。较高的药物暴露量与反应和使疾病长期稳定并具有可控毒性有关。基线时血浆细胞因子水平低表达的患者能够耐受较高剂量的伏立诺他，并从治疗中受益。基线细胞因子谱是有前途的潜在预测生物标志物。试验注册ClinicalTrials.gov，NCT01422499。2011年8月24日注册。较高的药物暴露量与反应和使疾病长期稳定并具有可控毒性有关。基线时血浆细胞因子水平低表达的患者能够耐受较高剂量的伏立诺他，并从治疗中受益。基线细胞因子谱是有前途的潜在预测生物标志物。试验注册ClinicalTrials.gov，NCT01422499。2011年8月24日注册。