Department of Clinical Research, Délégation Recherche Clinique Et Innovation, Centre Jean Perrin, 58 Rue Montalembert, 63011, Clermont-Ferrand, France.
INSERM U1240 IMoST, Université Clermont Auvergne, Clermont-Ferrand, France.
BMC Cancer. 2023 Apr 15;23(1):344. doi: 10.1186/s12885-023-10829-y.
Despite standard treatments including chemoradiotherapy with temozolomide (TMZ) (STUPP protocol), the prognosis of glioblastoma patients remains poor. AGuIX nanoparticles have a high radiosensitizing potential, a selective and long-lasting accumulation in tumors and a rapid renal elimination. Their therapeutic effect has been proven in vivo on several tumor models, including glioblastoma with a potential synergetic effect when combined with TMZ based chemoradiotherapy, and they are currently evaluated in 4 ongoing Phase Ib and II clinical trials in 4 indications (brain metastases, lung, pancreatic and cervix cancers) (> 100 patients received AGuIX). Thus, they could offer new perspectives for patients with newly diagnosed glioblastoma. The aim of this study is to determine the recommended dose of AGuIX as a radiosensitizer in combination with radiotherapy and TMZ during the concurrent radio-chemotherapy period for phase II (RP2D) and to estimate the efficacy of the combination.
NANO-GBM is a multicenter, phase I/II, randomized, open-label, non-comparative, therapeutic trial. According to a dose escalation scheme driven by a TITE-CRM design, 3 dose levels of AGuIX (50, 75 and 100 mg/kg) will be tested in phase I added to standard concomitant radio-chemotherapy. Patients with grade IV glioblastoma, not operated or partially operated, with a KPS ≥ 70% will be eligible for the study. The primary endpoints are i) for phase I, the RP2D of AGuIX, with DLT defined as any grade 3-4 NCI-CTCAE toxicity and ii) for phase II, the 6-month progression-free survival rate. The pharmacokinetics, distribution of nanoparticles, tolerance of the combination, neurological status, overall survival (median, 6-month and 12-month rates), response to treatment, and progression-free survival (median and 12-month rates) will be assessed as secondary objectives. Maximum sixty-six patients are expected to be recruited in the study from 6 sites.
The use of AGuIX nanoparticles could allow to overpass the radioresistance to the reference treatment of newly diagnosed glioblastomas that have the poorest prognosis (incomplete resection or biopsy only).
Clinicaltrials.gov: NCT04881032 , registered on April 30, 2021. Identifier with the French National Agency for the Safety of Medicines and Health Products (ANSM): N°Eudra CT 2020-004552-15.
version 3, 23 May 2022.
尽管采用替莫唑胺（TMZ）的放化疗标准治疗（STUPP 方案），胶质母细胞瘤患者的预后仍然很差。AGuIX 纳米颗粒具有高放射增敏作用，可选择性且持久地积聚在肿瘤中，并迅速从肾脏排出。其治疗效果已在几种肿瘤模型中得到证实，包括胶质母细胞瘤，与 TMZ 为基础的放化疗联合使用时具有潜在的协同作用，目前正在四项适应症（脑转移、肺、胰腺和宫颈癌）的四项正在进行的 Ib 期和 II 期临床试验中进行评估（>100 名患者接受了 AGuIX）。因此，它们可为新诊断的胶质母细胞瘤患者提供新的治疗前景。本研究的目的是确定 AGuIX 作为放射增敏剂与放疗和 TMZ 联合应用于 II 期（RP2D）同步放化疗期间的推荐剂量，并评估联合用药的疗效。
NANO-GBM 是一项多中心、I/II 期、随机、开放标签、非对照、治疗性试验。根据 TITE-CRM 设计驱动的剂量递增方案，将在 I 期研究中加入标准同步放化疗，测试 3 种 AGuIX 剂量水平（50、75 和 100mg/kg）。未经手术或部分手术的 IV 级胶质瘤患者，KPS≥70%将有资格参加研究。主要终点为 i）I 期研究中 AGuIX 的 RP2D，定义为任何 3-4 级 NCI-CTCAE 毒性的剂量限制性毒性（DLT），ii）II 期研究中 6 个月无进展生存率。药代动力学、纳米颗粒分布、联合用药的耐受性、神经状态、总生存率（中位值、6 个月和 12 个月生存率）、治疗反应和无进展生存率（中位值和 12 个月生存率）将作为次要终点进行评估。预计将从 6 个地点招募最多 66 名患者进行研究。
使用 AGuIX 纳米颗粒可以克服新诊断的胶质母细胞瘤对参考治疗的放射抵抗，而新诊断的胶质母细胞瘤的预后最差（不完全切除或仅活检）。
Clinicaltrials.gov：NCT04881032，于 2021 年 4 月 30 日注册。法国药品和健康产品安全局（ANSM）标识符：Eudra CT 2020-004552-15。
第 3 版，2022 年 5 月 23 日。
