University Hospital Basel, Division of Oncology, Dept. of Biomedicine, Petersgraben 4, 4031 Basel, Switzerland.
University College London Hospitals NHS Trust, Gynecological Oncology Team, 235 Euston Road, London NW1 2BU, United Kingdom.
Eur J Cancer. 2018 Jun;96:6-16. doi: 10.1016/j.ejca.2018.03.012. Epub 2018 Apr 13.
PQR309 is an orally bioavailable, balanced pan-phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin (mTOR) C1 and mTORC2 inhibitor.
This is an accelerated titration, 3 + 3 dose-escalation, open-label phase I trial of continuous once-daily (OD) PQR309 administration to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics in patients with advanced solid tumours. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D).
Twenty-eight patients were included in six dosing cohorts and treated at a daily PQR309 dose ranging from 10 to 150 mg. Common adverse events (AEs; ≥30% patients) included fatigue, hyperglycaemia, nausea, diarrhoea, constipation, rash, anorexia and vomiting. Grade (G) 3 or 4 drug-related AEs were seen in 13 (46%) and three (11%) patients, respectively. Dose-limiting toxicity (DLT) was observed in two patients at 100 mg OD (>14-d interruption in PQR309 due to G3 rash, G2 hyperbilirubinaemia, G4 suicide attempt; dose reduction due to G3 fatigue, G2 diarrhoea, G4 transaminitis) and one patient at 80 mg (G3 hyperglycaemia >7 d). PK shows fast absorption (T 1-2 h) and dose proportionality for C and area under the curve. A partial response in a patient with metastatic thymus cancer, 24% disease volume reduction in a patient with sinonasal cancer and stable disease for more than 16 weeks in a patient with clear cell Bartholin's gland cancer were observed.
The MTD and RP2D of PQR309 is 80 mg of orally OD. PK is dose-proportional. PD shows PI3K pathway phosphoprotein downregulation in paired tumour biopsies. Clinical activity was observed in patients with and without PI3K pathway dysregulation.
ClinicalTrials.gov # NCT01940133.
PQR309 是一种口服生物可利用的、平衡的磷脂酰肌醇-3-激酶（PI3K）、雷帕霉素靶蛋白（mTOR）C1 和 mTORC2 抑制剂。
这是一项加速滴定、3+3 剂量递增、开放性 I 期试验，评估连续每日一次（OD）PQR309 给药在晚期实体瘤患者中的安全性、药代动力学（PK）和药效学。主要目的是确定最大耐受剂量（MTD）和推荐的 II 期剂量（RP2D）。
28 例患者纳入 6 个剂量组，接受 10 至 150mg 每日 PQR309 治疗。常见不良反应（AE；≥30%患者）包括疲劳、高血糖、恶心、腹泻、便秘、皮疹、厌食和呕吐。分别有 13 例（46%）和 3 例（11%）患者发生 3 或 4 级药物相关 AE。2 例患者在 100mg OD 时出现剂量限制性毒性（DLT）（因 G3 皮疹、G2 高胆红素血症、G4 自杀企图导致 PQR309 中断>14d；因 G3 疲劳、G2 腹泻、G4 转氨酶升高导致剂量减少），1 例患者在 80mg 时发生（G3 高血糖>7d）。PK 显示快速吸收（T 1-2h）和 C 和曲线下面积的剂量比例性。一名转移性胸腺癌患者出现部分缓解，1 例鼻窦癌患者疾病体积减少 24%，1 例透明细胞巴氏腺癌患者疾病稳定超过 16 周。
PQR309 的 MTD 和 RP2D 为 80mg，每日口服一次。PK 呈剂量比例性。PD 显示配对肿瘤活检中 PI3K 通路磷酸化蛋白下调。在存在和不存在 PI3K 通路失调的患者中观察到临床活性。
ClinicalTrials.gov # NCT01940133。
