Meneses-Lorente Georgina, McIntyre Christine, Hsu Joy C, Thomas Marlene, Jacob Wolfgang, Adessi Celine, Weisser Martin
Roche Innovation Center Welwyn, Roche Pharma Research and Early Development, Roche Products Ltd, Hexagon Place, 6 Falcon Way, Welwyn Garden City, Hertfordshire, AL7 1TW, UK.
Roche Innovation Center New York, New York, USA.
Cancer Chemother Pharmacol. 2017 Jun;79(6):1239-1247. doi: 10.1007/s00280-017-3328-3. Epub 2017 May 11.
This study aimed at evaluating if pharmacokinetic and pharmacodynamic data from the first few patients treated with an investigational monoclonal antibody in a dose-escalation study can be used to guide the early initiation of potentially more efficacious combination regimens.
Emerging pharmacokinetic and pharmacodynamic data from the first nine patients treated with lumretuzumab (a glycoengineered anti-HER3 monoclonal antibody) monotherapy at doses from 100 to 400 mg q2w were used along with a pharmacokinetic model that incorporated target-mediated drug disposition to guide the selection of the starting dose for use in combination regimens.
The dose-escalation study investigated lumretuzumab doses up to 2000 mg q2w and a maximum tolerated dose was not reached. However, the model described in this report predicted linear lumretuzumab pharmacokinetics and >95% target saturation at doses ≥400 mg q2w. These data, along with safety data, contributed to the decision to begin dose-escalation studies in combination with cetuximab and erlotinib using a starting dose of 400 mg lumretuzumab. Pharmacokinetic data from patients treated with lumretuzumab 400-2000 mg q2w in combination regimens were consistent with the model predictions.
PK/PD modelling of emerging clinical data might accelerate development programs by enabling additional parts of a trial to commence before completion of the monotherapy part. The dose and schedule of lumretuzumab were optimised for concomitant therapy at doses substantially below the highest dose investigated.
本研究旨在评估在剂量递增研究中，接受研究性单克隆抗体治疗的最初几名患者的药代动力学和药效学数据是否可用于指导早期启动可能更有效的联合治疗方案。
使用从100至400mg q2w剂量接受鲁美妥珠单抗（一种糖工程化抗HER3单克隆抗体）单药治疗的前9名患者的新出现的药代动力学和药效学数据，以及纳入了靶点介导药物处置的药代动力学模型，来指导联合治疗方案起始剂量的选择。
剂量递增研究考察了高达2000mg q2w的鲁美妥珠单抗剂量，未达到最大耐受剂量。然而，本报告中描述的模型预测，鲁美妥珠单抗药代动力学呈线性，且在≥400mg q2w剂量下靶点饱和度>95%。这些数据以及安全性数据促使决定开始使用400mg鲁美妥珠单抗的起始剂量与西妥昔单抗和厄洛替尼联合进行剂量递增研究。联合治疗方案中接受400 - 2000mg q2w鲁美妥珠单抗治疗的患者的药代动力学数据与模型预测一致。
新出现的临床数据的PK/PD建模可能通过使试验的其他部分在单药治疗部分完成之前就开始，从而加速开发计划。鲁美妥珠单抗的剂量和给药方案针对联合治疗进行了优化，剂量大幅低于所研究的最高剂量。
