Development of wearable technology to enable therapy personalization of 177Lu DOTATATE for neuroendocrine tumors

对于转移性生长抑素受体2（SSTR 2）阳性神经内分泌肿瘤（NET）患者， 使用177 Lu-DOTATATE的靶向治疗大大增加了无进展生存期（PFS），如在 NETTER-1试验。对于用177 Lu处理的中肠NET，第20个月的PFS为65.2%（95%CI，50.0 - 76.8）。 与接受60 mg奥曲肽长链的对照组中的10.8%（95% CI，3.5 - 23.0）相比， 每四周释放一次。现在177 Lu-DOTATATE已经获得FDA的批准，它可能会成为标准 有症状的NET患者和转移性扩散患者的护理。然而，FDA包装说明 要求患者接受四次7.4 GBq治疗，无论身高、体重、性别或患者健康状况如何。 传统上，靶向放射性核素治疗是基于对主要危险器官的剂量进行个性化的。 规范化治疗与个体化医疗的理想背道而驰， 对许多患者的治疗剂量。用于177 Lu的器官剂量测定估计的传统方法（即，6.65 天的半衰期）需要在约7天内展开3-4次纵向成像会话。这是昂贵的，利用一个 需要大量的临床资源，并且给患者带来负担。该项目的目标是实现精确的 个体化的177 Lu-DOTATATE器官剂量测定，而不需要连续成像会话（注： 约98%接受177 Lu-DOTATATE治疗的患者的OAR是肾脏）。我们将通过以下方式实现这一目标： 开发廉价的、可穿戴的监测技术，以允许通过以下方式进行定量测量： 病人在家。这将支持准确估计单个风险器官（OAR）的洗脱， 使得能够对每个治疗疗程进行精确的器官剂量测定， 基于个性化器官剂量测定信息的治疗次数。在目标1中，衡量方法 来自可穿戴、低成本、个性化家庭剂量测定（PHD）带的个体器官剂量信息将被 使用Monte Carlo模拟工具。在目标2中，用于器官特定剂量的原型PHD带 估计会被伪造。该皮带将由6-15个小型光谱计数探测器组成， <750克，取决于结合到带中的检测器的数量。它将被设计得很轻 重量，形状拟合，并将有对齐功能，以实现一致的日常穿着/定位的 带相对于病人的内部器官。传送带还将配备电子设备， 通过Wi-Fi获取、存储数据并将其发送到安全网站，以进行近真实的时间数据监控。在目标3中，a 使用简化方案比较个体器官剂量测定估计的小型试点研究（即，一 输注后24小时的SPECT/CT和PHD带测量加上7-21 PHD带在家测量） 相对于3个时间点（即，第1、4和7天）临床SPECT/CT成像（即，在许多情况下， 美国以外的国家）进行。在本项目结束时，创建和利用PHD带的方法将 已经过测试和验证，PHD带将准备在早期临床试验中进行评估。

For patients with metastatic, somatostatin-receptor-2 (SSTR2) positive neuroendocrine tumors (NETs), targeted therapy using 177Lu-DOTATATE greatly increases progression-free survival (PFS), as shown in the NETTER-1 trial. PFS at month 20 was 65.2% (95% CI, 50.0 - 76.8) for midgut NETs treated with 177Lu- DOTATATE alone compared to 10.8% (95% CI, 3.5 - 23.0) in a control group receiving 60 mg octreotide long- acting release every 4 weeks. Now that 177Lu-DOTATATE has FDA approval it likely will become the standard of care for symptomatic NET patients and those with metastatic spread. However, FDA package instructions call for patients to receive four 7.4 GBq treatments, regardless of size, weight, gender or patient health status. Traditionally, targeted radionuclide therapies are personalized based upon dose to the main organs at risk. Standardized therapy is counter to the ideals of personalized medicine and will lead to non-optimum therapeutic dosing for many patients. Traditional methods for organ dosimetry estimation for 177Lu (i.e., 6.65 day half-life) require 3-4 longitudinal imaging sessions spread out over ~7 days. This is expensive, utilizes a lot of clinic resources and is burdensome to the patient. The goal of this project is to enable precise individualized 177Lu-DOTATATE organ dosimetry without requiring serial imaging sessions (note: the main OAR for ~98% of patients receiving 177Lu-DOTATATE therapy is the kidneys). We will accomplish this by developing inexpensive, wearable monitoring technology to allow quantitative measurements to be made by the patient at home. This will support accurate estimation of the washout from individual organs at risk (OAR), enabling accurate organ dosimetry for each treatment session thereby allowing physicians to individually tailor the number of treatments based upon personalized organ dosimetry information. In Aim 1 methods to measure individual organ dose information from a wearable, low cost, personalized home dosimetry (PHD) belt will be developed using Monte Carlo simulation tools. In Aim 2, a prototype PHD belt for organ specific dose estimation will be fabricated. The belt will consist of 6-15 small, spectrographic counting detectors and weigh <750 grams depending upon the number of detectors incorporated into the belt. It will be designed to be light weight, form fitting and will have alignment features to enable consistent day to day wearing/positioning of the belt with respect to the patient’s internal organs. The belt will further be equipped with electronics that can acquire, store and send the data via Wi-Fi to a secure web-site for near real time data monitoring. In Aim 3, a small pilot study to compare individual organ dosimetry estimates using a streamlined protocol (i.e., one SPECT/CT and PHD belt measurement at 24 hr post infusion plus 7-21 PHD belt at home measurements) versus 3-time point (i.e., 1, 4 and 7 day) in-clinic SPECT/CT imaging (i.e., standard protocol followed in many non-US countries) will be conducted. At the end of this project, methods to create and utilize a PHD belt will have been tested and validated and the PHD belt will be ready for evaluation in an early phase clinical trial.