Early Phase Clinical Trials in Imaging and Image-Guided Interventions

影像学和图像引导干预的早期临床试验

• 批准号: 8948733
• 负责人: AeRang Kim
• 金额: $ 27.28万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-23 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8948733
• 关键词: Active immunity; Acute; Address; Adjuvant Therapy; Adult; Adverse effects; Affect; Algorithms; Biological Markers; Body Temperature; Cancer Patient; Cells; Child; Childhood; Childhood Solid Neoplasm; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; DNA Repair; Deposition; Development; Devices; Dose; Doxorubicin; Drug Delivery Systems; Drug Extravasation; Drug Formulations; Drug Kinetics; Encapsulated; Equilibrium; Failure; Focused Ultrasound Therapy; Goals; Heat shock proteins; Heating; Hyperthermia; Image; Immune; Immune response; Immunologic Adjuvants; Immunologic Surveillance; Inflammatory; Ionizing radiation; Late Effects; Learning; Lesion; Liposomal Doxorubicin; Liposomes; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Childhood Neoplasm; Maps; Maximum Tolerated Dose; Modality; Monitor; Nature; Newly Diagnosed; Nonionizing Radiation; Outcome; Pediatric Oncology; Perfusion; Permeability; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Property; Protein Inhibition; Quality of life; Radiosurgery; Reaction; Recurrence; Refractory; Relapse; Research; Signal Pathway; Site; Solid Neoplasm; Superficial Lesion; System; Systemic disease; T-Lymphocyte; Technology; Temperature; Testing; Therapeutic; Time; Toxic effect; Treatment Protocols; Tumor Antigens; Tumor Tissue; Tumor-Derived; Vascular Permeabilities; adaptive immunity; base; chemotherapeutic agent; chemotherapy; cold temperature; effective therapy; flexibility; heating technology; image guided; image guided intervention; improved; non-invasive imaging; novel; novel strategies; outcome forecast; pediatric patients; phase 1 study; pre-clinical; public health relevance; response; treatment planning; tumor; tumor growth; tumor microenvironment; young adult

 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.

 描述（由申请人提供）：尽管采用了包括手术、放疗和化疗在内的多种治疗方法，但患有转移性、复发性或难治性实体瘤的儿童和年轻人的预后仍然差得令人无法接受，并且在过去三十年中没有显着改善。最大剂量强化的限制以及联合治疗的急性和晚期影响是巨大的，该提案的目标是通过最大化当前治疗效果的方法来提高儿科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、实时温度映射和使用完全非接触式的外部涂抹器在空间上明确的能量沉积来提供受控的热量传递。溶血热敏脂质体阿霉素 (LTLD) 是一种热激活脂质体阿霉素制剂，具有热激活释放阿霉素的独特特性，阿霉素是一种活性物质。 MR-HIFU 引起的低温局部加热的灵活性和控制提供了与 LTLD 结合使用的理想系统。该疗法的协同作用是多方面的，包括增强肿瘤血管的渗透性，增强药物的外渗以及随后在靶肿瘤中高浓度的阿霉素、热休克蛋白的表达、DNA修复的抑制以及免疫反应的刺激，我们建议进行LTLD联合的一期试验。 MR-HIFU 在患有难治性或复发性实体瘤的儿童和年轻人中诱导轻度高热 (HT)，我们将 1) 确定 LTLD 的最大耐受剂量、毒性特征和药代动力学，2) 确定该方法的可行性、准确性和精密度。用于维持大容量轻度 HT 的 MR-HIFU 算法，以及 3) 确定接受 LTLD 治疗的儿童和年轻人中适应性免疫和肿瘤衍生微泡的生物标志物的变化MR-HIFU 诱导轻度 HT 并与靶标和脱靶病灶的反应相关，这项临床研究代表了对难治性实体瘤儿童的 LTLD 的首次评估，也是首次评估 MR-HIFU 诱导的轻度 HT 的优先暴露能力。 MR-HIFU 的空间精度和基于实时成像和温度监测的精确治疗计划、缺乏电离辐射以及 MR-HIFU 的非侵入性使得肿瘤局部高浓度阿霉素不会增加全身副作用。药物-设备组合是一种极具吸引力的方式，可以很容易地将其纳入新诊断和复发实体瘤的现有治疗方案中，有可能改变我们治疗癌症儿童的方式。