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Cholecystokinin 2 Receptor Agonist 177Lu-PP-F11N for Radionuclide Therapy of Medullary Thyroid Carcinoma: Results of the Lumed Phase 0a Study
The Journal of Nuclear Medicine ( IF 9.1 ) Pub Date : 2020-04-01 , DOI: 10.2967/jnumed.119.233031
Christof Rottenburger , Guillaume P. Nicolas , Lisa McDougall , Felix Kaul , Michal Cachovan , A. Hans Vija , Roger Schibli , Susanne Geistlich , Anne Schumann , Tilman Rau , Katharina Glatz , Martin Behe , Emanuel R. Christ , Damian Wild

Treatment of patients with advanced medullary thyroid carcinoma (MTC) is still a challenge. For more than 2 decades, it has been known that the cholecystokinin 2 receptor is a promising target for the treatment of MTC with radiolabeled minigastrin analogs. Unfortunately, kidney toxicity has precluded their therapeutic application so far. In 6 consecutive patients, we evaluated with advanced 3-dimensional dosimetry whether improved minigastrin analog 177Lu-DOTA-(d-Glu)6-Ala-Tyr-Gly-Trp-Nle-Asp-PheNH2 (177Lu-PP-F11N) is a suitable agent for the treatment of MTC. Methods: Patients received 2 injections of about 1 GBq (∼80 μg) of 177Lu-PP-F11N with and without a solution of succinylated gelatin (SG, a plasma expander used for nephroprotection) in a random crossover sequence to evaluate biodistribution, pharmacokinetics, and tumor and organ dosimetry. An electrocardiogram was obtained and blood count and blood chemistry were measured up to 12 wk after the administration of 177Lu-PP-F11N to assess safety. Results: In all patients, 177Lu-PP-F11N accumulation was visible in tumor tissue, stomach, and kidneys. Altogether, 13 tumors were eligible for dosimetry. The median absorbed doses for tumors, stomach, kidneys, and bone marrow were 0.88 (interquartile range [IQR]: 0.85–1.04), 0.42 (IQR: 0.25–1.01), 0.11 (IQR: 0.07–0.13), and 0.028 (IQR: 0.026–0.034) Gy/GBq, respectively. These doses resulted in median tumor-to-kidney dose ratios of 11.6 (IQR: 8.11–14.4) without SG and 13.0 (IQR: 10.2–18.6) with SG; these values were not significantly different (P = 1.0). The median tumor-to-stomach dose ratio was 3.34 (IQR: 1.14–4.70). Adverse reactions (mainly hypotension, flushing, and hypokalemia) were self-limiting and not higher than grade 1. Conclusion: 177Lu-PP-F11N accumulates specifically in MTC at a dose that is sufficient for a therapeutic approach. With a low kidney and bone marrow radiation dose, 177Lu-PP-F11N shows a promising biodistribution. The dose-limiting organ is most likely the stomach. Further clinical studies are necessary to evaluate the maximum tolerated dose and the efficacy of 177Lu-PP-F11N.



中文翻译:

胆囊收缩素2受体激动剂177 Lu-PP-F11N用于髓样甲状腺癌的放射性核素治疗:Lumed 0a期研究的结果

晚期甲状腺髓样癌(MTC)患者的治疗仍然是一个挑战。二十多年来,人们已经知道胆囊收缩素2受体是用放射性标记的小胃泌素类似物治疗MTC的有希望的靶标。不幸的是,到目前为止,肾脏毒性阻止了它们的治疗应用。在连续的6例患者中,我们用先进的3维剂量测定法评估了minigastrin类似物177 Lu-DOTA-(d - Glu)6 -Ala-Tyr-Gly-Trp-Nle-Asp-PheNH 2177 Lu-PP-F11N )是治疗MTC的合适药物。方法:患者接受2次注射,每次注射约1 GBq(〜80μg)177Lu-PP-F11N,有和没有琥珀酰明胶(SG,一种用于肾保护的血浆扩展剂)溶液,以随机交叉顺序进行,以评估生物分布,药代动力学以及肿瘤和器官剂量。在服用177 Lu-PP-F11N后至12周为止,均获得了心电图,并测量了血液计数和血液化学,以评估安全性。结果:在所有患者中,177Lu-PP-F11N的积累在肿瘤组织,胃和肾脏中可见。总共有13个肿瘤符合剂量学标准。肿瘤,胃,肾和骨髓的平均吸收剂量为0.88(四分位间距[IQR]:0.85–1.04),0.42(IQR:0.25–1.01),0.11(IQR:0.07–0.13)和0.028(IQR) :0.026–0.034)Gy / GBq。这些剂量导致没有SG的肿瘤与肾脏的中位剂量比为11.6(IQR:8.11-14.4),而有SG的中位数为13.0(IQR:10.2-18.6);这些值没有显着差异(P = 1.0)。肿瘤与胃的中位剂量比为3.34(IQR:1.14–4.70)。不良反应(主要是低血压,潮红和低钾血症)是自限性的,不高于1级。结论: 177Lu-PP-F11N专门以足以用于治疗的剂量在MTC中积累。177 Lu-PP-F11N具有较低的肾脏和骨髓辐射剂量,显示出良好的生物分布。剂量限制器官很可能是胃。需要进一步的临床研究以评估177 Lu-PP-F11N的最大耐受剂量和疗效。

更新日期:2020-04-23
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