First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors.
First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors.
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DOI：
10.1158/1078-0432.ccr-14-0947
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发表时间：
2015-01-01
期刊：
影响因子：
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通讯作者：
de Bono JS
中科院分区：
文献类型：
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作者：
Sarker D;Ang JE;Baird R;Kristeleit R;Shah K;Moreno V;Clarke PA;Raynaud FI;Levy G;Ware JA;Mazina K;Lin R;Wu J;Fredrickson J;Spoerke JM;Lackner MR;Yan Y;Friedman LS;Kaye SB;Derynck MK;Workman P;de Bono JS
这项首次人体剂量递增试验评估了pictilisib（GDC-0941）的安全性、耐受性、最大耐受剂量（MTD）、剂量限制性毒性（DLT）、药代动力学、药效学和初步临床活性，pictilisib是一种口服、强效和选择性的I类磷脂酰肌醇-3-激酶（PI 3 K）抑制剂。60名实体瘤患者接受了15至450 mg的14个剂量水平的pictilisib，每日一次，最初每28天在第1-21天及之后，利用选定剂量水平的连续给药。药效学研究包括18F-FDG-PET，以及对富血小板血浆和肿瘤组织中磷酸化AKT和S6核糖体蛋白的评估。Pictilisib耐受性良好。最常见的毒性为1-2级恶心、皮疹和疲乏，而DLT为3级斑丘疹（450 mg，3例患者中的2例; 330 mg，7例患者中的1例）。药代动力学特征与剂量成比例，支持每日一次给药。在MTD剂量给药后3小时，富含血小板的血浆中磷酸化丝氨酸-473 AKT的水平被抑制>90%，并且在与AUC > 20 μ M. hr相关的pictilisib剂量下，肿瘤中磷酸化丝氨酸-473 AKT的水平被抑制>90%。在32名可评估患者中的7名中，血浆胰岛素和葡萄糖水平显著增加，并且18F-FDG摄取降低>25%，证实了靶调节。根据RECIST和GCIG-CA 125标准，分别有1例V600 E BRAF突变型黑色素瘤患者和另1例铂难治性上皮性卵巢癌患者表现出PTEN缺失和PIK 3CA扩增，表现出部分缓解。Pictilisib安全给药，具有与剂量成比例的药代动力学特征，在≥ 100 mg剂量水平下具有靶向药效学活性，并具有抗肿瘤活性体征。推荐的II期剂量为330 mg每日一次连续给药。
This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal tolerated dose (MTD), dose limiting toxicities (DLTs), pharmacokinetics, pharmacodynamics and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent and selective inhibitor of the Class I phosphatidylinositol-3-kinases (PI3K). Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450mg once-daily, initially on days 1-21 every 28 days and later, utilizing continuous dosing for selected dose levels. Pharmacodynamic studies incorporated 18F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma and tumor tissue. Pictilisib was well-tolerated. The most common toxicities were grade 1-2 nausea, rash and fatigue while the DLT was grade 3 maculopapular rash (450mg, 2 of 3 patients; 330mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in platelet rich plasma at 3 hours post-dose at the MTD and in tumor at pictilisib doses associated with AUC >20uM.hr. Significant increase in plasma insulin and glucose levels, and >25% decrease in 18F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100mg and signs of antitumor activity. The recommended Phase II dose was continuous dosing at 330mg once-daily.