First-in-human阶段我研究copanlisib(湾80 - 6946),静脉pan-class我磷脂酰肌醇3-kinase抑制剂,在晚期实体肿瘤患者和非霍奇金淋巴瘤。

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Patnaik阿普曼LJ, Tolcher啊,帕帕多普洛斯KP, Beeram M, Rasco DW,维斯GJ, Sachdev JC,查达米,富尔克米,Ejadi年代,Mountz JM, Lotze MT,托莱多FG,楚E,杰弗斯M,佩纳C,夏C,赖夫年代,Ramanathan Genvresse我家乡

First-in-human阶段我研究copanlisib(湾80 - 6946),静脉pan-class我磷脂酰肌醇3-kinase抑制剂,在晚期实体肿瘤患者和非霍奇金淋巴瘤。

安10月杂志。2016;27 (10):1928 - 40。doi: 10.1093 / annonc / mdw282。

PubMed ID

27672108 (在PubMed

]

文摘

背景:评估安全、耐受性、药物动力学,和最大耐受剂量(MTD)的copanlisib,一个磷脂酰肌醇3-kinase抑制剂,在晚期实体肿瘤患者或非霍奇金淋巴瘤(NHL)。患者和方法:第一阶段增大剂量研究包括晚期实体肿瘤患者或NHL,和一群2型糖尿病患者。患者接受三周静脉输液copanlisib每28天周期的剂量范围0.1 - -1.2毫克/公斤。血浆copanlisib水平对药物动力学进行了分析。生物标志物分析包括PIK3CA、喀斯特、BRAF和PTEN突变状态和PTEN免疫组织化学。全身[(18)F]氟脱氧葡萄糖正电子发射断层扫描((18)正)进行了基线和后第一剂量评估早期的药效学作用。连续血糖和胰岛素水平进行评估。结果:57例接受治疗。0.8毫克/公斤copanlisib MTD。最常见的治疗相关的不良事件是恶心和瞬态高血糖。 Copanlisib exposure was dose-proportional with no accumulation; peak exposure positively correlated with transient hyperglycemia post-infusion. Sixteen of 20 patients treated at the MTD had reduced (18)FDG-PET uptake; 7 (33%) had a reduction >25%. One patient achieved a complete response (CR; endometrial carcinoma exhibiting both PIK3CA and PTEN mutations and complete PTEN loss) and two had a partial response (PR; both metastatic breast cancer). Among the nine NHL patients, all six with follicular lymphoma (FL) responded (one CR and five PRs) and one patient with diffuse large B-cell lymphoma had a PR by investigator assessment; two patients with FL who achieved CR (per post hoc independent radiologic review) were on treatment >3 years. CONCLUSION: Copanlisib, dosed intermittently on days 1, 8, and 15 of a 28-day cycle, was well tolerated and the MTD was determined to be 0.8 mg/kg. Copanlisib exhibited dose-proportional pharmacokinetics and promising anti-tumor activity, particularly in patients with NHL. CLINICALTRIALSGOV: NCT00962611; https://clinicaltrials.gov/ct2/show/NCT00962611.

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药物

Copanlisib