Safety, Pharmacokinetics, and Dosimetry of a Long-Acting Radiolabeled Somatostatin Analog Lu-DOTA-EB-TATE in Patients with Advanced Metastatic Neuroendocrine Tumors.

Radiolabeled somatostatin analog therapy has become an established treatment method for patients with well to moderately differentiated unresectable or metastatic neuroendocrine tumors (NETs). The most frequently used somatostatin analogs in clinical practice are octreotide and octreotate. However, both peptides showed suboptimal retention within tumors. The aim of this first-in-humans study is to explore the safety and dosimetry of a long-acting radiolabeled somatostatin analog, Lu-1, 4, 7, 10-tetra-azacyclododecane-1, 4, 7, 10-tetraacetic acid-Evans blue-octreotate (Lu-DOTA-EB-TATE). Eight patients (6 men and 2 women; age range, 27-61 y) with advanced metastatic NETs were recruited. Five patients received a single dose, 0.35-0.70 GBq (9.5-18.9 mCi), of Lu-DOTA-EB-TATE and underwent serial whole-body planar and SPECT/CT scans at 2, 24, 72, 120, and 168 h after injection. The other 3 patients received intravenous injection of 0.28-0.41 GBq (7.5-11.1 mCi) of Lu-DOTATATE for the same imaging acquisition procedures at 1, 3, 4, 24, and 72 h after injection. The dosimetry was calculated using the OLINDA/EXM 1.1 software. Administration of Lu-DOTA-EB-TATE was well tolerated, with no adverse symptoms being noticed or reported in any of the patients. Compared with Lu-DOTATATE, Lu-DOTA-EB-TATE showed extended circulation in the blood and achieved a 7.9-fold increase of tumor dose delivery. The total-body effective doses were 0.205 ± 0.161 mSv/MBq for Lu-DOTA-EB-TATE and 0.174 ± 0.072 mSv/MBq for Lu-DOTATATE. Significant dose delivery increases to the kidneys and bone marrow were also observed in patients receiving Lu-DOTA-EB-TATE compared with those receiving Lu-DOTATATE (3.2 and 18.2-fold, respectively). By introducing an albumin-binding moiety, Lu-DOTA-EB-TATE showed remarkably higher uptake and retention in NETs as well as significantly increased accumulation in the kidneys and red marrow. It has great potential to be used in peptide receptor radionuclide therapy for NETs with lower dose and less frequency of administration.