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: 9340123
• 负责人: AeRang Kim
• 金额: $ 23.56万
• 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 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9340123
• 关键词: Ablation; 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 Inhibition; Deposition; Development; Devices; Dose; Doxorubicin; Drug Delivery Systems; Drug Extravasation; Drug Kinetics; Encapsulated; Equilibrium; Focused Ultrasound Therapy; Formulation; Goals; Heat shock proteins; Heating; Hyperthermia; Image; Immune; Immune Evasion; Immune response; Immunization; Immunologic Adjuvants; Immunologic Surveillance; Inflammatory; Ionizing radiation; Late Effects; Learning; Lesion; Liposomal Doxorubicin; Liposomes; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Childhood Neoplasm; Maximum Tolerated Dose; Modality; Monitor; Nature; Newly Diagnosed; Operative Surgical Procedures; Pediatric Oncology; Perfusion; Permeability; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Property; Quality of life; Radiation; 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 Failure; 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; microvesicles; non-invasive imaging; novel strategies; novel therapeutics; outcome forecast; pediatric patients; phase 1 study; pre-clinical; public health relevance; response; survival outcome; 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）：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，尽管进行了包括手术、放疗和化疗在内的多模式治疗，但在过去的三十年中没有显著改善。目前的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巨大的。该提案的目标是通过最大限度地提高当前治疗效果同时最大限度地减少相关并发症的方法来提高儿科癌症患者的治愈率和生活质量。 磁共振引导高强度聚焦超声（MR-HIFU）通过精确的图像引导、实时温度标测和空间明确的能量沉积，使用完全无创和非电离的外部施加器提供受控的热量输送。溶血热敏性多柔比星脂质体（LTLD）是多柔比星脂质体的热激活制剂，具有多柔比星热激活释放的独特性质，多柔比星是大多数儿科实体瘤的活性剂。由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。这种疗法的协同效应是多方面的，包括增强肿瘤脉管系统的渗透性、增强药物外渗和随后靶向肿瘤中高浓度的多柔比星、热休克蛋白的表达、抑制DNA修复和刺激免疫应答。 我们提出了一项LTLD联合MR-HIFU诱导的轻度高温（HT）治疗儿童和年轻成人难治性或复发性实体瘤的I期试验。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）确定用于维持大体积轻度HT的MR-HIFU算法的可行性、准确性和精密度，和3）确定用LTLD和MR治疗的儿童和年轻人中获得性免疫和肿瘤衍生微泡的生物标志物的变化。高强度聚焦超声可诱导轻度HT，且与靶区和脱靶区的反应相关。 拟议的临床研究代表了难治性实体瘤儿童中LTLD的首次评估和MR-HIFU诱导轻度HT的首次评估。优先将肿瘤暴露于高局部浓度的多柔比星而不增加全身副作用的能力，以及基于实时成像和温度监测的空间准确性和精确治疗计划、电离辐射的缺乏和MR-HIFU的非侵入性性质，使这种药物-装置组合成为极具吸引力的模式。这种新方法可以很容易地结合到现有的治疗方案中，用于新诊断和复发的实体瘤，可能会改变我们治疗儿童癌症的方式。