Early Phase Clinical Trials in Imaging and Image-Guided Interventions

 描述(申请人提供)：患有转移性、复发性或难治性实体肿瘤的儿童和年轻人的预后仍然很差，而且在过去30年中没有显著改善，尽管进行了包括手术、放射和化疗在内的多种治疗。目前的治疗方法已经达到了最大剂量强化的极限，联合治疗的急性和晚期效应是显著的。这项建议的目标是通过在最大限度地提高当前治疗效果的同时将相关并发症降至最低的方法来提高儿童癌症患者的治愈率和生活质量。磁共振引导的高强度聚焦超声(MR-HIFU)通过精确的图像引导、实时温度映射以及使用完全非侵入性和非电离的外部敷贴器在空间上精确地沉积能量来提供受控的热传递。溶温敏感阿霉素脂质体(LTLD)是阿霉素脂质体的热激活制剂，具有热激活释放阿霉素的独特特性，阿霉素是大多数儿科实体肿瘤中的活性物质。MR-HIFU对低温局部加热的灵活性和可控性为与LTLD结合使用提供了理想的系统。这种治疗的协同作用是多方面的，包括增强肿瘤血管的通透性，促进药物的外渗，随后靶向肿瘤中高浓度的阿霉素，热休克蛋白的表达，抑制DNA修复，以及刺激免疫反应。我们提出了一项LTLD联合MR-HIFU诱导的儿童和年轻人难治性或复发实体瘤的轻度热疗(HT)的1期试验。我们将1)确定LTLD的最大耐受量、毒性分布和药代动力学，2)确定MR-HIFU算法维持大容量轻度HT的可行性、准确性和精密度，3)测定接受LTLD和MR-HIFU治疗的儿童和年轻人获得性免疫和肿瘤衍生微囊的生物标志物的变化，并与靶区和非靶区病变的反应相关。这项拟议的临床研究是对难治性实体肿瘤儿童的LTLD的首次评估，也是对MR-HIFU诱导的轻度HT的首次评估。能够优先将肿瘤暴露于局部高浓度的阿霉素而不会增加全身副作用，再加上基于实时成像和温度监测的空间准确性和精确的治疗计划，缺乏电离辐射，以及MR-HIFU的非侵入性，使这种药物-设备组合成为一种非常有吸引力的方式。这种新的方法可以很容易地纳入新诊断和复发的实体肿瘤的现有治疗方案中，潜在地改变了我们治疗癌症儿童的方式。

 DESCRIPTION (provided by applicant): Prognosis for children and young adults with metastatic, relapsed, or refractory solid tumors remains unacceptably poor and has not improved significantly over the past three decades despite multimodality treatment including surgery, radiation, and chemotherapy. Current approaches have reached the limits of maximal dose intensification, and the acute and late effects of combination therapy are substantial. The goal of this proposal is to improve the cure rate and quality of life in pediatric cancer patients through approaches that maximize effects of current therapy while minimizing associated complications. Magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) provides controlled delivery of heat through precise image guidance, real-time temperature mapping, and spatially well-defined deposition of energy using an external applicator that is completely non-invasive and non-ionizing. Lyso-thermosensitive liposomal doxorubicin (LTLD) is a heat-activated formulation of liposomal doxorubicin with the unique property of heat-activated release of doxorubicin, an active agent in most pediatric solid tumors. The flexibility and control over low temperature local heating induced by MR-HIFU provides an ideal system to be used in conjunction with LTLD. The synergistic effects of this therapy are manifold and include enhanced permeability of the tumor vasculature, enhanced extravasation of the drug and subsequent high concentrations of doxorubicin in the targeted tumor, the expression of heat shock proteins, inhibition of DNA repair, and stimulation of immune responses. We propose a phase 1 trial of LTLD combined with MR-HIFU induced mild hyperthermia (HT) in children and young adults with refractory or relapsed solid tumors. We will 1) determine the maximum tolerated dose, toxicity profile, and pharmacokinetics of LTLD, 2) determine the feasibility, accuracy and precision of the MR- HIFU algorithm for sustaining large volume mild HT, and 3) determine the changes in biomarkers of adaptive immunity and tumor derived microvesicles in children and young adults treated with LTLD and MR-HIFU induced mild HT and correlate with response in target and off target lesions. The proposed clinical research represents the first assessment of LTLD in children with refractory solid tumors and the first assessment of MR-HIFU induced mild HT. The ability to preferentially expose tumors to high local concentration of doxorubicin without increasing systemic side effects in conjunction with the spatial accuracy and precise treatment planning based on real-time imaging and temperature monitoring, lack of ionizing radiation, and non-invasive nature of MR-HIFU make this drug-device combination an extremely attractive modality. This novel approach can be readily incorporated into existing treatment regimens for both newly diagnosed and recurrent solid tumors, potentially transforming the way we treat children with cancer.