A phase I open-labeled, single-arm, dose-escalation, study of dichloroacetate (DCA) in patients with advanced solid tumors
A phase I open-labeled, single-arm, dose-escalation, study of dichloroacetate (DCA) in patients with advanced solid tumors
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DOI：
10.1007/s10637-015-0221-y
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发表时间：
2015-06-01
影响因子：
3.4
通讯作者：
Michelakis, Evangelos D.
中科院分区：
文献类型：
--
作者：
Chu, Quincy Siu-Chung;Sangha, Randeep;Michelakis, Evangelos D.
目的临床前研究表明，二氯醋酸盐（DCA）可逆转瓦尔堡效应，抑制肿瘤生长。本项I期研究旨在评估口服DCA在晚期实体瘤患者中的安全性、推荐II期剂量（RP 2D）和药代动力学（PK）特征。患者和方法24例晚期实体恶性肿瘤患者采用标准3 + 3方案入组，起始剂量为6.25 mg/kg，每日两次（BID）。持续28天为一周期的治疗，直至疾病进展、毒性反应或撤回知情同意。在第1周期的第1天和第15天以及后续周期的第1天收集PK样本。PET成像（（18）F-FDG摄取）作为反应的潜在生物标志物进行了研究。结果23例可评价患者接受DCA 6.25 mg/kg和12.5 mg/kg BID两种剂量治疗，中位治疗周期各2个。6.25 mg/kg BID队列中未发生DLT，因此剂量递增。12.5 mg/kg BID组7例患者中有3例发生DLT（疲乏、呕吐、腹泻）。另外13例患者接受6.25 mg/kg BID治疗。大多数毒性为1-2级，最常见的是疲劳、神经病变和恶心。没有观察到任何反应，8名患者病情稳定。癌症患者中的DCA PK特征与先前发表的数据一致。患者间PK值和神经病变的变异性较高。观察到DCA谷水平逐渐升高，并且随着DCA治疗时间的延长，（18）F-FDG摄取呈下降趋势。结论口服DCA的RP 2D为6.25 mg/kg BID。在未来的试验中需要仔细监测毒性。
Purpose Preclinical evidence suggests dichloroacetate (DCA) can reverse the Warburg effect and inhibit growth in cancer models. This phase 1 study was undertaken to assess the safety, recommended phase 2 dose (RP2D), and pharmacokinetic (PK) profile of oral DCA in patients with advanced solid tumors. Patients and Methods Twenty-four patients with advanced solid malignancies were enrolled using a standard 3 + 3 protocol at a starting dose of 6.25 mg/kg twice daily (BID). Treatment on 28 days cycles was continued until progression, toxicity, or consent withdrawal. PK samples were collected on days 1 and 15 of cycle 1, and day 1 of subsequent cycles. PET imaging ((18) F-FDG uptake) was investigated as a potential biomarker of response. Results Twenty-three evaluable patients were treated with DCA at two doses: 6.25 mg/kg and 12.5 mg/kg BID (median of 2 cycles each). No DLTs occurred in the 6.25 mg/kg BID cohort so the dose was escalated. Three of seven patients had DLTs (fatigue, vomiting, diarrhea) at 12.5 mg/kg BID. Thirteen additional patients were treated at 6.25 mg/kg BID. Most toxicities were grade 1-2 with the most common being fatigue, neuropathy and nausea. No responses were observed and eight patients had stable disease. The DCA PK profile in cancer patients was consistent with previously published data. There was high variability in PK values and neuropathy among patients. Progressive increase in DCA trough levels and a trend towards decreased (18) F-FDG uptake with length of DCA therapy was observed. Conclusions The RP2D of oral DCA is 6.25 mg/kg BID. Toxicities will require careful monitoring in future trials.