Division of Cancer Medicine, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Melanoma Institute Australia and University of Sydney, New South Wales, Australia. Westmead Institute for Cancer Research, Westmead Millennium Institute, and Department of Medical Oncology, Westmead Hospital, Sydney, New South Wales, Australia.
Clin Cancer Res. 2014 Sep 1;20(17):4449-58. doi: 10.1158/1078-0432.CCR-14-0887. Epub 2014 Jun 23.
Dabrafenib is a selective, potent ATP-competitive inhibitor of the BRAFV600-mutant kinase that has demonstrated efficacy in clinical trials. We report the rationale for dose selection in the first-in-human study of dabrafenib, including pharmacokinetics, tissue pharmacodynamics, 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) pharmacodynamics, and dose-response relationship.
Dabrafenib was administered orally once, twice (BID), or three times daily (TID). Selected dose cohorts were expanded to collect adequate data on safety, pharmacokinetics, or pharmacodynamics. A recommended phase II dose (RP2D) was chosen based on safety, pharmacokinetic, pharmacodynamic, and response data.
One hundred and eighty-four patients were enrolled and treated with doses ranging from 12 mg once daily to 300 mg BID in 10 cohorts. Pharmacokinetic assessment of dabrafenib demonstrated a less-than-dose-proportional increase in exposure after repeat dosing above 150 mg BID. Similar to parent drug concentrations, exposure for all metabolites demonstrated less-than-dose-proportional increases. Predicted target inhibition of pERK (>80%) was achieved at 150 mg BID, with a similar magnitude of inhibition at higher doses in BRAFV600 mutation melanoma biopsy samples. Although there was large variability between patients, FDG uptake decreased with higher daily doses in patients with BRAFV600 mutation-positive melanoma. A favorable activity and tolerability profile was demonstrated at 150 mg BID. There was no improvement with TID dosing compared with BID dosing, based on FDG-PET and tumor response analyses in patients with melanoma.
The RP2D of dabrafenib was determined to be 150 mg BID after considering multiple factors, including pharmacokinetics, tissue pharmacodynamics, FDG-PET pharmacodynamics, and the dose-response relationship. A maximum tolerated dose for dabrafenib was not determined.
达拉非尼是一种选择性、强效的 ATP 竞争性 BRAFV600 突变激酶抑制剂，在临床试验中显示出疗效。我们报告了达拉非尼首次人体研究中剂量选择的原理，包括药代动力学、组织药效学、2[18F]氟-2-脱氧-D-葡萄糖正电子发射断层扫描（FDG-PET）药效学和剂量反应关系。
达拉非尼口服一次、两次（BID）或每天三次（TID）。选择了一些剂量组进行扩展，以收集足够的安全性、药代动力学或药效学数据。根据安全性、药代动力学、药效学和反应数据选择了推荐的 II 期剂量（RP2D）。
共招募了 184 名患者，接受了从每天 12 毫克到每天 300 毫克 BID 的 10 个剂量组的治疗。达拉非尼的药代动力学评估表明，重复给药超过 150 毫克 BID 后，暴露量呈非剂量比例增加。与母体药物浓度相似，所有代谢物的暴露量也呈非剂量比例增加。在 150 毫克 BID 时，pERK 的预测靶抑制（>80%）得到了实现，在 BRAFV600 突变黑色素瘤活检样本中，更高剂量时的抑制程度相似。尽管患者之间存在很大的变异性，但在 BRAFV600 突变阳性黑色素瘤患者中，随着每日高剂量的给药，FDG 摄取量减少。在 150 毫克 BID 时，表现出良好的活性和耐受性。根据黑色素瘤患者的 FDG-PET 和肿瘤反应分析，与 BID 相比，TID 剂量没有改善。
考虑到药代动力学、组织药效学、FDG-PET 药效学和剂量反应关系等多种因素，确定达拉非尼的 RP2D 为 150 毫克 BID。未确定达拉非尼的最大耐受剂量。
