背景:胰腺导管腺癌的致密间质是药物递送的主要障碍。为了增加局部药物扩散梯度,高剂量的化疗剂阿霉素可以使用超声介导的热疗从热敏脂质体(ThermoDox®)在肿瘤靶标释放。PanDox被设计为1期单中心研究,以研究增强对不可手术的胰腺导管腺癌成年患者的药物输送。该研究比较了单一循环的常规阿霉素或ThermoDox®与聚焦超声诱导的热疗的靶向药物释放。
方法:患有不可切除的胰腺导管腺癌的成年人被分配接受单周期的单独阿霉素(A组)或ThermoDox®聚焦超声诱导的热疗(B组),基于患者和肿瘤特定的安全条件。B组的参与者将通过身体外聚焦超声(FUS)对肿瘤进行全身麻醉和预热。而不是采用侵入式测温法,超声参数来自患者特定的治疗计划模型,以达到41°C的药物释放目标温度。然后将ThermoDox®与进一步的超声暴露同时输注。在治疗后使用高效液相色谱法分析来自所有患者的靶向部位处的肿瘤活检,以定量递送至肿瘤的多柔比星。主要终点定义为肿瘤内阿霉素总浓度的统计学显着提高,将接受脂质体药物与FUS的患者的样品与单独的游离药物进行比较。参与者在治疗后随访21天,以评估次要终点,包括放射学评估,以根据实体瘤的正电子发射断层扫描反应标准(PERCIST)标准测量肿瘤活性的变化,不良事件和患者报告的症状。
结论:这项早期研究建立在先前针对肝脏肿瘤的工作基础上,以研究使用超声介导的热疗增强化疗递送是否可以转化为胰腺导管腺癌的基质致密环境。如果成功,它可能预示着一种新的方法来管理这些难以治疗的肿瘤。
背景:ClinicalTrials.gov标识符:NCT04852367。2022年4月21日注册。EudraCT编号:2019-003950-10(注册2019年)Iras项目ID:272253(注册2019年)伦理编号:20/EE/0284。
BACKGROUND: The dense stroma of pancreatic ductal adenocarcinomas is a major barrier to drug delivery. To increase the local drug diffusion gradient, high doses of chemotherapeutic agent doxorubicin can be released from thermally-sensitive liposomes (ThermoDox®) using ultrasound-mediated hyperthermia at the tumour target. PanDox is designed as a Phase 1 single centre
study to investigate enhancing drug delivery to adult patients with non-operable pancreatic ductal adenocarcinomas. The
study compares a single cycle of either conventional doxorubicin alone or ThermoDox® with focused ultrasound-induced hyperthermia for targeted drug release.
METHODS: Adults with non-resectable pancreatic ductal adenocarcinoma are allocated to receive a single cycle of either doxorubicin alone (Arm A) or ThermoDox® with focused ultrasound-induced hyperthermia (Arm B), based on patient- and tumour-specific safety conditions. Participants in Arm B will undergo a general anaesthetic and pre-heating of the tumour by extra-corporal focused ultrasound (
FUS). Rather than employing invasive thermometry, ultrasound parameters are derived from a patient-specific treatment planning model to reach the 41 °C target temperature for drug release. ThermoDox® is then concurrently infused with further ultrasound exposure. Tumour biopsies at the targeted site from all patients are analysed post-treatment using high performance liquid chromatography to quantify doxorubicin delivered to the tumour. The primary endpoint is defined as a statistically significant enhancement in concentration of total intra-tumoural doxorubicin, comparing samples from patients receiving liposomal drug with
FUS to free drug alone. Participants are followed for 21 days post-treatment to assess secondary endpoints, including radiological assessment to measure changes in tumour activity by Positron Emission Tomography Response Criteria in Solid Tumours (PERCIST) criteria, adverse events and patient-reported symptoms.
CONCLUSIONS: This early phase
study builds on previous work targeting tumours in the liver to investigate whether enhancement of chemotherapy delivery using ultrasound-mediated hyperthermia can be translated to the stroma-dense environment of pancreatic ductal adenocarcinoma. If successful, it could herald a new approach towards managing these difficult-to-treat tumours.
BACKGROUND: ClinicalTrials.gov Identifier: NCT04852367 . Registered 21st April 2022. EudraCT number: 2019-003950-10 (Registered 2019) Iras Project ID: 272253 (Registered 2019) Ethics Number: 20/EE/0284.