Department of Neurosurgery, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Unit of Cancer Stem Cells, ISBReMIT, IRCCS CasaSollievo della Sofferenza, San Giovanni Rotondo (FG), Italy.
Mol Cancer. 2023 Aug 10;22(1):129. doi: 10.1186/s12943-023-01835-6.
This Phase 1 study evaluates the intra- and peritumoral administration by convection enhanced delivery (CED) of human recombinant Bone Morphogenetic Protein 4 (hrBMP4) - an inhibitory regulator of cancer stem cells (CSCs) - in recurrent glioblastoma.
In a 3 + 3 dose escalation design, over four to six days, fifteen recurrent glioblastoma patients received, by CED, one of five doses of hrBMP4 ranging from 0·5 to 18 mg. Patients were followed by periodic physical, neurological, blood testing, magnetic resonance imaging (MRI) and quality of life evaluations. The primary objective of this first-in-human study was to determine the safety, dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of hrBMP4. Secondary objectives were to assess potential efficacy and systemic exposure to hrBMP4 upon intracerebral infusion.
Intra- and peritumoral infusion of hrBMP4 was safe and well-tolerated. We observed no serious adverse events related to this drug. Neither MTD nor DLT were reached. Three patients had increased hrBMP4 serum levels at the end of infusion, which normalized within 4 weeks, without sign of toxicity. One patient showed partial response and two patients a complete (local) tumor response, which was maintained until the most recent follow-up, 57 and 30 months post-hrBMP4. Tumor growth was inhibited in areas permeated by hrBMP4.
Local delivery of hrBMP4 in and around recurring glioblastoma is safe and well-tolerated. Three patients responded to the treatment. A complete response and long-term survival occurred in two of them. This warrants further clinical studies on this novel treatment targeting glioblastoma CSCs.
ClinicaTrials.gov identifier: NCT02869243.
本研究为 I 期临床试验，评估了采用对流增强递送（CED）技术在复发性胶质母细胞瘤中瘤内和瘤周递送人重组骨形态发生蛋白 4（hrBMP4）的安全性和耐受性。hrBMP4 是一种癌症干细胞（CSCs）的抑制调节因子。
在 3+3 剂量递增设计中，15 例复发性胶质母细胞瘤患者接受为期 4-6 天的 CED 治疗，hrBMP4 剂量范围为 0.5-18mg，共 5 个剂量。通过定期的体格检查、神经学检查、血液检查、磁共振成像（MRI）和生活质量评估来随访患者。该首次人体研究的主要目的是确定人重组骨形态发生蛋白 4（hrBMP4）的安全性、剂量限制性毒性（DLT）和最大耐受剂量（MTD）。次要目标是评估颅内输注后潜在的疗效和系统暴露情况。
hrBMP4 的瘤内和瘤周递呈是安全且耐受良好的。我们未观察到与该药物相关的严重不良事件。未达到 MTD 或 DLT。在输注结束时，有 3 名患者的血清 hrBMP4 水平升高，4 周内恢复正常，无毒性迹象。1 名患者表现出部分缓解，2 名患者表现出完全（局部）肿瘤缓解，在接受 hrBMP4 治疗后的最近一次随访中，2 名患者的肿瘤缓解持续时间分别为 57 个月和 30 个月。在 hrBMP4 渗透的区域，肿瘤生长受到抑制。
局部递呈 hrBMP4 治疗复发性胶质母细胞瘤是安全且耐受良好的。有 3 名患者对治疗有反应。其中 2 名患者出现完全缓解和长期生存。这为靶向胶质母细胞瘤 CSCs 的新型治疗方法提供了进一步的临床研究依据。
ClinicalTrials.gov 标识符：NCT02869243。
