Somatostatin receptors in the diagnosis and treatment of thyroid cancer

我们计划在患有转移性、放射性碘无应答的嗜铬细胞甲状腺癌的成人患者中进行一项1/2期、开放标签研究，以评估递增剂量的177 Lu-DOTA-EB-TATE的3剂量方案的安全性、剂量测定和疗效。 拟定适应症为治疗成人生长抑素受体阳性放射性碘（RAI）无应答转移性Hrthle细胞甲状腺（HTC）癌。 我们假设本研究将解决以下问题： 评价177 Lu-DOTA-EB-TATE是否安全和可耐受。 177 Lu-DOTA-EB-TATE治疗转移性HTC的早期疗效分析 根据贝叶斯最佳间隔I/II期事件发生时间（TITE-BOIN 12），确定177 Lu-DOTA-EB-TATE的最佳剂量，其特征为疗效和毒性之间的最佳权衡 主要目的： 1/2期 根据1/2期临床试验的TITE-BOIN 1/2设计，确定177 Lu-DOTA-EB-TATE治疗转移性HTC的最佳剂量，该剂量既安全又显示足够的疗效 从发生治疗相关不良事件的患者数量评估177Lu DOTA EB TATE的安全性。 确定177 Lu DOTA EB TATE递增剂量的剂量限制性毒性（DLT），肾脏累积暴露量高达27戈伊，骨髓累积暴露量不超过2戈伊，最多3个周期，间隔82周。 评估177 Lu DOTA EB TATE改善转移性RAI无应答HTC受试者末次研究药物治疗后6个月无进展生存期（PFS）的疗效。 次要目的： 确定177 Lu-DOTA-EB-TATE每个周期后患者的剂量测定，包括以下内容： O 177 Lu-DOTA-EB-TATE在肝脏、脾脏、肾脏、全身和血池中的停留时间。 O 每个器官的比吸收剂量（戈伊/GBq）（使用OLINDA/EXM中实施的MIRD方法） O 累积吸收器官剂量（戈伊） O 使用基于血液的方法的骨髓剂量。 O 标准化摄取值（SUV）标准化为可辨别靶病变的最大瘦体重（SULmax） O 肝脏、脾脏、肾脏、骨髓和垂体（如可见）中的SULmax。 根据RECIST 1.1标准，评估177 Lu DOTA EB TATE治疗后6个月和12个月的客观缓解率（ORR）。根据RECIST 1.1定义，具有靶病灶和非靶病灶的患者将被纳入分析。 评估研究药物末次给药后6个月和12个月随访标志时每个病灶的比吸收剂量与按照RECIST 1.1标准定义的肿瘤缓解之间的相关性。 评估肿瘤标志物甲状腺球蛋白（Tg）和抗Tg抗体从治疗前至研究药物末次给药后6个月和12个月的变化。 使用经甲状腺疾病患者验证的ThyPRO问卷，评估基线和每个治疗周期后以及治疗完成后6个月和12个月的生活质量（QoL）。 将入组最多18名患有转移性RAI无应答或RAI非嗜酸性Hrthle细胞甲状腺癌的18岁或以上男性和女性成人，以获得15名可评价患者（每个队列3名患者，最多5个队列）。

We plan to conduct a Phase 1/2, Open-Label Study of the Safety, Dosimetry and Efficacy of a 3-Dose Regimen of Escalating Doses of 177Lu-DOTA-EB-TATE in Adult Patients with Metastatic, Radioactive Iodine Non-Responsive Hrthle-Cell Thyroid Cancer The proposed indication is for the treatment of somatostatin receptor-positive radioactive iodine (RAI) non-responsive metastatic Hrthle cell thyroid (HTC) cancer in adults. We hypothesize that this study will address the following: Evaluate if 177Lu-DOTA-EB-TATE is safe and tolerable. Analyze early efficacy of 177Lu-DOTA-EB-TATE in therapy of metastatic HTC. Establish the optimal dose of 177Lu-DOTA-EB-TATE that is characterized by an optimal trade-off between efficacy and toxicity based on Bayesian optimal interval phase I/II time-to-event (TITE-BOIN12) Primary Objectives: Phase 1/2 To determine the optimal dose of 177Lu-DOTA-EB-TATE that is both safe and shows sufficient efficacy for treatment of metastatic HTC based on TITE-BOIN12 design of phase 1/2 clinical trial To evaluate the safety of 177Lu DOTA EB TATE assessed from the number of patients with treatment-related adverse events. To identify the dose-limiting toxicities (DLTs) of escalating doses of 177Lu DOTA EB TATE up to 27 Gy cumulative exposure to the kidneys and not exceeding 2 Gy cumulative exposure to the bone marrow in up to 3 cycles 82 weeks apart. To assess the efficacy of 177Lu DOTA EB TATE to improve upon progression-free survival (PFS) at 6 months after the last cycle of the study drug in participants with metastatic RAI-non-responsive HTC. Secondary Objectives: To determine dosimetry in patients following each cycle of 177Lu-DOTA-EB-TATE, including the following: o Residence time of 177Lu-DOTA-EB-TATE including liver, spleen, kidneys, whole body and blood pool. o Specific absorbed dose per organ (Gy/GBq) (using MIRD method as implemented in OLINDA/EXM) o Cumulative absorbed organ doses (Gy) o Bone Marrow dose using blood-based method. o Standardized uptake value (SUV) normalized to lean body mass for maximum (SULmax) in discernible target lesions o SULmax in liver, spleen, kidneys, bone marrow and pituitary if visible. To assess the objective response rate (ORR) after the therapy with 177Lu DOTA EB TATE at 6- and 12-months post-treatment defined by RECIST 1.1 criteria. Patients with target and non-target lesions per RECIST 1.1 definitions will be included in the analysis. To assess the association between the specific absorbed dose per lesion with the tumor response as defined by RECIST 1.1 criteria at 6 and 12 months follow up landmark post last dose of the study drug. To assess the tumor marker thyroglobulin (Tg) and anti-Tg antibodies change from pre-treatment to 6- and 12-months post last dose of the study drug. To assess the quality of life (QoL) at baseline and after each treatment cycle as well as at 6- and 12-months landmarks post completion of the therapy, using ThyPRO questionnaire, validated for patients with thyroid disorders. Up to 18 male and female adults, 18 years or older, with metastatic RAI-non-responsive or RAI non-avid Hrthle cell thyroid cancer will be enrolled in order to have 15 evaluable patients (3 patients per cohort, up to 5 cohorts).