PURPOSE GDC-0084 is an oral, brain-penetrant small molecule inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR). A first-in-human, Phase I study was conducted in patients with recurrent high-grade glioma. EXPERIMENTAL DESIGN GDC-0084 was administered orally, once-daily to evaluate safety, pharmacokinetics (PK) and activity. Fluorodeoxyglucose positron emission tomography (FDG-PET) was performed to measure metabolic responses. RESULTS Forty-seven heavily pretreated patients enrolled in eight cohorts (2-65 mg). Dose-limiting toxicities (DLTs) included one case of Grade 2 bradycardia and Grade 3 myocardial ischemia (15 mg), Grade 3 stomatitis (45 mg) and 2 cases of Grade 3 mucosal inflammation (65 mg); the maximum tolerated dose (MTD) was 45 mg/day. GDC-0084 demonstrated linear and dose-proportional PK, with a half-life (~19 hr) supportive of once-daily dosing. At 45 mg/day, steady-state concentrations exceeded pre-clinical target concentrations producing antitumor activity in xenograft models. FDG-PET in 7 of 27 patients (26%) showed metabolic partial response. At doses ≥ 45 mg/day, a trend towards decreased median SUV in normal brain was observed, suggesting central nervous system penetration of drug. In 2 resection specimens, GDC-0084 was detected at similar levels in tumor and brain tissue, with a brain tissue/tumor to plasma ratio of > 1 and > 0.5 for total and free drug, respectively. Best overall response was stable disease in 19 patients (40%), and progressive disease in 26 patients (55%); 2 patients (4%) were non-evaluable. CONCLUSIONS GDC-0084 demonstrated classic PI3K/mTOR-inhibitor related toxicities. FDG-PET and concentration data from brain tumor tissue suggest that GDC-0084 crossed the blood-brain barrier.

中文翻译：

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一项人类首次I期研究，用于评估进行性或复发性高级神经胶质瘤患者的脑穿透性PI3K / mTOR抑制剂GDC-0084。

目的GDC-0084是磷酸肌醇3激酶（PI3K）和雷帕霉素（mTOR）的哺乳动物靶标的口服，脑渗透小分子抑制剂。在复发性高级别神经胶质瘤患者中进行了一项人类首次I期研究。实验设计GDC-0084每天口服一次，以评估安全性，药代动力学（PK）和活性。进行了氟脱氧葡萄糖正电子发射断层扫描（FDG-PET）以测量代谢反应。结果47例经过严格治疗的患者纳入了8个队列（2-65 mg）。限剂量毒性（DLTs）包括1例2级心动过缓和3级心肌缺血（15 mg），3级口腔炎（45 mg）和2例3级粘膜炎症（65 mg）；最大耐受剂量（MTD）为45毫克/天。GDC-0084具有线性和剂量比例的PK，半衰期（〜19 hr）支持每天一次的给药。在异种移植模型中，每天45 mg的稳态浓度超过临床前目标浓度，从而产生抗肿瘤活性。27名患者中有7名（26％）的FDG-PET表现出代谢部分反应。在≥45 mg /天的剂量下，观察到正常脑中SUV的下降趋势，这表明中枢神经系统已渗透药物。在2个切除标本中，在肿瘤和脑组织中检测到GDC-0084的水平相似，总和游离药物的脑组织/肿瘤与血浆比率分别> 1和> 0.5。最佳的总体反应是稳定的疾病19例（40％），进行性疾病26例（55％）。2名患者（4％）无法评估。结论GDC-0084证明了经典的PI3K / mTOR抑制剂相关毒性。