一项评估考匹司他联合吉西他滨或顺铂联合吉西他滨治疗晚期癌症患者的 I 期剂量递增研究。
Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer.
机构信息
Department of Gastrointestinal Oncology, Moffitt Cancer Center, 12902 USF Magnolia Drive, Number 1, Tampa, FL 33612, USA.
Department of Medical Oncology, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55905, USA.
出版信息
Br J Cancer. 2018 Feb 20;118(4):462-470. doi: 10.1038/bjc.2017.428. Epub 2018 Jan 18.
BACKGROUND
Copanlisib is a pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α/δ activity that has demonstrated clinical activity and manageable safety when administered as monotherapy in a phase II study. Combination therapy may overcome compensatory signalling that could occur with PI3K pathway inhibition, resulting in enhanced inhibitory activity, and preclinical studies of copanlisib with gemcitabine have demonstrated potent anti-tumour activity in vivo.
METHODS
A phase I, open-label, dose-escalation study to evaluate the safety, tolerability and recommended phase II dose (RP2D) of copanlisib with gemcitabine or with cisplatin plus gemcitabine (CisGem) in patients with advanced malignancies, including an expansion cohort in patients with biliary tract cancer (BTC) at the RP2D of copanlisib plus CisGem. Copanlisib and gemcitabine were administered on days 1, 8 and 15 of a 28-day cycle; maximum tolerated dose (MTD) and RP2D of copanlisib were determined. Copanlisib plus CisGem was administered on days 1 and 8 of a 21-day cycle; pharmacokinetics and biomarkers were assessed.
RESULTS
Fifty patients received treatment as follows: dose-escalation cohorts, n=16; copanlisib plus CisGem cohort, n=14; and BTC expansion cohort, n=20. Copanlisib 0.8 mg kg plus gemcitabine was the MTD and RP2D for both combinations. Common treatment-emergent adverse events included nausea (86%), hyperglycaemia (80%) and decreased platelet count (80%). Copanlisib exposure displayed a dose-proportional increase. No differences were observed upon co-administration of CisGem. Response rates were as follows: copanlisib plus gemcitabine, 6.3% (one partial response in a patient with peritoneal carcinoma); copanlisib plus CisGem, 12% (one complete response and three partial responses all in patients with BTC (response rate 17.4% in patients with BTC)). Mutations were detected in PIK3CA (1 out of 43), KRAS (10 out of 43) and BRAF (2 out of 22), with phosphate and tensin homologue protein loss in 41% (12 out of 29).
CONCLUSIONS
Copanlisib plus CisGem demonstrated a manageable safety profile, favourable pharmacokinetics, and potentially promising clinical response.
背景
Copanlisib 是一种泛 PI3K 抑制剂，对 PI3K-α/δ 有显著的抑制作用。在一项 II 期研究中，Copanlisib 作为单药治疗时，具有临床活性和可管理的安全性。联合治疗可能会克服 PI3K 通路抑制时可能发生的代偿性信号，从而增强抑制活性，Copanlisib 联合吉西他滨的临床前研究显示出体内有很强的抗肿瘤活性。
方法
一项开放标签、剂量递增的 I 期研究，旨在评估 Copanlisib 联合吉西他滨或联合顺铂加吉西他滨（CisGem）治疗晚期恶性肿瘤患者的安全性、耐受性和推荐的 II 期剂量（RP2D），在 Copanlisib 联合 CisGem 的 RP2D 时，在胆道癌（BTC）患者中进行扩展队列研究。Copanlisib 和吉西他滨在 28 天周期的第 1、8 和 15 天给药；确定最大耐受剂量（MTD）和 Copanlisib 的 RP2D。Copanlisib 联合 CisGem 在 21 天周期的第 1 和 8 天给药；评估药代动力学和生物标志物。
结果
50 名患者接受了以下治疗：剂量递增队列，n=16；Copanlisib 联合 CisGem 队列，n=14；BTC 扩展队列，n=20。Copanlisib 0.8mg/kg 联合吉西他滨是两种联合用药的 MTD 和 RP2D。常见的治疗相关不良事件包括恶心（86%）、高血糖（80%）和血小板计数减少（80%）。Copanlisib 的暴露量呈剂量比例增加。与 CisGem 联合用药时未观察到差异。反应率如下：Copanlisib 联合吉西他滨，6.3%（1 例腹膜癌患者有部分缓解）；Copanlisib 联合 CisGem，12%（3 例 BTC 患者完全缓解，3 例部分缓解（BTC 患者的缓解率为 17.4%））。在 43 例患者中检测到 PIK3CA（1 例）、KRAS（10 例）和 BRAF（2 例）的突变，在 29 例患者中有 41%（12 例）的磷酸酶和张力蛋白同源物蛋白丢失。
结论
Copanlisib 联合 CisGem 显示出可管理的安全性、良好的药代动力学和有潜力的临床反应。
Zotero 插件