Cancer Research UK, Cambridge Research Institute, University of Cambridge Robinson Way, Cambridge CB2 0RE, UK.
Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0RE, UK.
Br J Cancer. 2018 Mar 20;118(6):793-801. doi: 10.1038/bjc.2017.495. Epub 2018 Feb 13.
The Notch pathway is frequently activated in cancer. Pathway inhibition by γ-secretase inhibitors has been shown to be effective in pre-clinical models of pancreatic cancer, in combination with gemcitabine.
A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered per os weekly, in combination with gemcitabine administered intravenously on days 1, 8 and 15 (28 day cycle) at 800 or 1000 mg m, was performed to determine the safety of combination treatment and the recommended phase 2 dose (RP2D). Secondary and tertiary objectives included tumour response, plasma and tumour MK-0752 concentration, and inhibition of the Notch pathway in hair follicles and tumour.
Overall, 44 eligible patients (performance status 0 or 1 with adequate organ function) received gemcitabine and MK-0752 as first or second line treatment for pancreatic cancer. RP2Ds of MK-0752 and gemcitabine as single agents could be combined safely. The Bayesian algorithm allowed further dose escalation, but pharmacokinetic analysis showed no increase in MK-0752 AUC (area under the curve) beyond 1800 mg once weekly. Tumour response evaluation was available in 19 patients; 13 achieved stable disease and 1 patient achieved a confirmed partial response.
Gemcitabine and a γ-secretase inhibitor (MK-0752) can be combined at their full, single-agent RP2Ds.
Notch 通路在癌症中经常被激活。在胰腺癌的临床前模型中，与吉西他滨联合使用 γ-分泌酶抑制剂已被证明具有疗效。
一项多中心、非随机贝叶斯自适应设计研究，每周口服 MK-0752，联合静脉注射吉西他滨，第 1、8 和 15 天（28 天周期），剂量为 800 或 1000mg/m²，旨在确定联合治疗的安全性和推荐的 2 期剂量（RP2D）。次要和次要目标包括肿瘤反应、血浆和肿瘤 MK-0752 浓度以及毛囊和肿瘤中 Notch 通路的抑制。
共有 44 名符合条件的患者（表现状态 0 或 1，器官功能正常）接受吉西他滨和 MK-0752 作为胰腺癌的一线或二线治疗。MK-0752 和吉西他滨作为单药的 RP2D 可以安全联合。贝叶斯算法允许进一步增加剂量，但药代动力学分析表明，每周一次增加到 1800mg 不会增加 MK-0752 的 AUC（曲线下面积）。在 19 名可评估肿瘤反应的患者中，13 名患者疾病稳定，1 名患者获得确认的部分缓解。
吉西他滨和 γ-分泌酶抑制剂（MK-0752）可以在其最大、单药的 RP2D 下联合使用。
