Somatostatin receptors in the diagnosis and treatment of thyroid cancer

我们计划进行一项1/2期开放标签研究，研究三剂量递增剂量的177Lu-DOTA-EB-Tate在转移性、放射性碘无反应的甲状腺癌患者中的安全性、剂量学和疗效 建议的适应症是用于治疗生长抑素受体阳性的放射性碘(RAI)无反应性转移性Hrthle细胞甲状腺癌(HTC)。 我们假设这项研究将解决以下问题： 评估177Lu-DOTA-EB-Tate是否安全和耐受性。 ~(177)Lu-DOTA-EB-Tate治疗转移性HTC近期疗效分析 根据贝叶斯最优间隔I/II期事件发生时间(TITE-BOIN12)确定以疗效和毒性最佳权衡为特征的177Lu-DOTA-EB-Tate的最佳剂量 主要目标： 阶段1/2 根据Tite-BOIN12设计的1/2期临床试验确定安全有效的177 Lu-DOTA-EB-Tate治疗转移性HTC的最佳剂量 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。 为了确定177Lu DOTA EB Tate在间隔82周的3个周期内对肾脏的累积照射高达27GY和对骨髓的累积照射不超过2GY的剂量限制毒性(DLT)。 为了评估177Lu DOTA EB Tate在研究药物最后一个周期结束后6个月改善转移性RAI无反应HTC参与者的无进展生存期(PFS)的有效性。 次要目标： 为确定177Lu-DOTA-EB-Tate每个周期患者的剂量学，包括以下内容： O~(177)Lu-DOTA-EB-Tate的滞留时间包括肝、脾、肾、全身和血池。 O每器官比吸收剂量(Gy/Gbq)(使用Olinda/exm中实施的MIRD方法) O累积吸收器官剂量(GY) O骨髓剂量采用血液法。 O标准化摄取值(SUV)归一化为瘦体重最大值(SULmax)在可识别的靶区 肝、脾、肾、骨髓和脑下垂体中可见SULmax。 按RECIST 1.1标准评价177Lu DOTA EB Tate治疗后6个月和12个月的客观有效率(ORR)。符合RECIST 1.1定义的靶区和非靶区病变的患者将包括在分析中。 为了评估每个病灶的比吸收剂量与RECIST 1.1标准所定义的肿瘤反应之间的相关性，在最后一次服用研究药物后的6个月和12个月进行里程碑式的随访。 观察治疗前、末次服药后6个月和12个月肿瘤标志物甲状腺球蛋白(TG)和抗TG抗体的变化。 为了评估基线和每个治疗周期后以及治疗结束后6个月和12个月的里程碑处的生活质量(QOL)，使用ThyPRO问卷，对甲状腺疾病患者进行验证。 最多18名成年男性和女性，18岁或以上，患有转移性RAI无反应或RAI无反应的Hrthle细胞甲状腺癌，将被纳入15名可评估的患者(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).