Department of Tumor Immunology, Radboudumc, Nijmegen, The Netherlands.
Oncode Institute, Nijmegen, The Netherlands.
BMJ Open. 2021 Nov 30;11(11):e050725. doi: 10.1136/bmjopen-2021-050725.
The undiminished need for more effective cancer treatments stimulates the development of novel cancer immunotherapy candidates. The archetypical cancer immunotherapy would induce robust, targeted and long-lasting immune responses while simultaneously circumventing immunosuppression in the tumour microenvironment. For this purpose, we developed a novel immunomodulatory nanomedicine: PRECIOUS-01. As a PLGA-based nanocarrier, PRECIOUS-01 encapsulates a tumour antigen (NY-ESO-1) and an invariant natural killer T cell activator to target and augment specific antitumour immune responses in patients with NY-ESO-1-expressing advanced cancers.
This open-label, first-in-human, phase I dose-escalation trial investigates the safety, tolerability and immune-modulatory activity of increasing doses of PRECIOUS-01 administered intravenously in subjects with advanced NY-ESO-1-expressing solid tumours. A total of 15 subjects will receive three intravenous infusions of PRECIOUS-01 at a 3-weekly interval in three dose-finding cohorts. The trial follows a 3+3 design for the dose-escalation steps to establish a maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D). Depending on the toxicity, the two highest dosing cohorts will be extended to delineate the immune-related parameters as a readout for pharmacodynamics. Subjects will be monitored for safety and the occurrence of dose-limiting toxicities. If the MTD is not reached in the planned dose-escalation cohorts, the RP2D will be based on the observed safety and immune-modulatory activity as a pharmacodynamic parameter supporting the RP2D. The preliminary efficacy will be evaluated as an exploratory endpoint using the best overall response rate, according to Response Evaluation Criteria in Solid Tumors V.1.1.
The Dutch competent authority (CCMO) reviewed the trial application and the medical research ethics committee (CMO Arnhem-Nijmegen) approved the trial under registration number NL72876.000.20. The results will be disseminated via (inter)national conferences and submitted for publication to a peer-reviewed journal.
NCT04751786.
对更有效癌症治疗方法的迫切需求推动了新型癌症免疫疗法候选药物的发展。典型的癌症免疫疗法应该能够诱导强大、靶向和持久的免疫反应，同时避免肿瘤微环境中的免疫抑制。为此，我们开发了一种新型免疫调节纳米药物：PRECIOUS-01。作为一种基于 PLGA 的纳米载体，PRECIOUS-01 包封了一种肿瘤抗原（NY-ESO-1）和一种不变自然杀伤 T 细胞激活剂，以针对和增强表达 NY-ESO-1 的晚期癌症患者的特定抗肿瘤免疫反应。
这是一项开放标签、首次人体、I 期剂量递增试验，研究了在表达 NY-ESO-1 的晚期实体瘤患者中静脉内给予递增剂量 PRECIOUS-01 的安全性、耐受性和免疫调节活性。总共 15 名受试者将在三个剂量递增队列中每 3 周接受三次 PRECIOUS-01 静脉输注。该试验采用 3+3 设计进行剂量递增步骤，以确定最大耐受剂量（MTD）和/或推荐的 II 期剂量（RP2D）。根据毒性情况，将两个最高剂量组扩展到阐明作为药效学读出的免疫相关参数。将对受试者进行安全性监测和剂量限制性毒性的发生情况。如果在计划的剂量递增队列中未达到 MTD，则 RP2D 将基于观察到的安全性和免疫调节活性作为支持 RP2D 的药效学参数。根据实体瘤反应评估标准 1.1 版，使用最佳总缓解率作为探索性终点评估初步疗效。
荷兰主管当局（CCMO）审查了试验申请，医学研究伦理委员会（CMO Arnhem-Nijmegen）在登记号 NL72876.000.20 下批准了该试验。结果将通过（国际）会议传播，并提交给同行评议的期刊发表。
NCT04751786。
