Safety, Pharmacokinetics and Dosimetry of a Long-lasting Radiolabeled Somatostatin Analogue ¹⁷⁷Lu-DOTA-EB-TATE in Patients with Advanced Metastatic Neuroendocrine Tumors: A Phase 1 First-in-human Study

Objectives: With therapeutic radioisotopes such as yttrium-90 and/or lutetium-177, radiolabeled somatostatin analogue therapy has become a well-accepted treatment for patients with well to moderately differentiated unresectable or metastatic neuroendocrine tumors (NETs), allowing the targeted delivery of radionuclides directly to tumor cells which express high levels of somatostatin receptors (SSTRs). However, the peptides clear fast from the blood through the kidneys and which also affects the accumulation of radioactivity within tumor, therefore the dose delivered has to be given by adding intravenous infusion dose and treatment cycles. Many attempts have been made to increase the half-lives with effective longer action. The aim of this study focuses on a first-in-human, first-in-class Phase I trial (NCT03308682) to explore the safety and dosimetry of a novel long-lasting radiolabeled somatostatin analogue using albumin as a reversible carrier for drug delivery, lutetium-177-1, 4, 7, 10-tetra-azacyclododecane-1, 4, 7, 10-tetraacetic acid-Evans blue-Tyr3-octreotate (¹⁷⁷Lu-DOTA-EB-TATE), and also assess the preliminary effects of administration in patients with advanced metastatic neuroendocrine tumors.

Methods: Eight patients (6 male and 2 female; age range, 27-61 y, [mean ± SD, 44.0 ± 10.5y]; weight range, 50.0-86.0 kg [mean ± SD, 68.8 ± 13.2 kg]) with advanced metastatic neuroendocrine tumors were recruited from Peking Union Medical College Hospital (CAMS&PUMC, China). With ethics committee approval and written informed consent, each patient underwent whole-body ⁶⁸Ga-DOTATATE PET/CT and among them, 5 patients accepted intravenous injection with a single dose 0.35-0.70 GBq of ¹⁷⁷Lu-DOTA-EB-TATE within one week, and monitored at 2, 24, 72, 120 and 168 h after ¹⁷⁷Lu-DOTA-EB-TATE administration with serial whole body planar and SPECT/CT images acquired, the other 3 patients accepted 0.28-0.41 GBq of ¹⁷⁷Lu-DOTATATE within one week and monitored at 1, 3, 4, 24 and 72 h with the same imaging acquisition procedures. Blood samples were collected at different time points for gamma counting. The dosimetry calculation was performed according to the joint EANM/MIRD dosimetry guidance and calculated using the OLINDA/EXM software. Complete physical examination and vital signs, blood count, biochemistry, immunology analyses were performed immediately before and 1, 3, and 7 days after the injection of ¹⁷⁷Lu-DOTA-EB-TATE and 3 months follow up visit.

Results: Administration of ¹⁷⁷Lu-DOTA-EB-TATE was well tolerated, with no adverse symptoms being noticed or reported during the entire procedure and 3 months follow-up in any of the patients. The total effective dose equivalent and effective dose were 0.2048 ± 0.1605 and 0.0804 ± 0.0500 mSv/MBq for ¹⁷⁷Lu-DOTA-EB-TATE and 0.1735 ± 0.0722 and 0.0693 ± 0.0317 mSv/MBq for ¹⁷⁷Lu-DOTATATE. The organs of liver, kidneys, bone marrow and total body received higher doses (mGy/MBq) for ¹⁷⁷Lu-DOTA-EB-TATE than ¹⁷⁷Lu-DOTATATE (0.3468 vs. 0.2247, 1.1494 vs. 0.3603, 0.0582 vs. 0.0032, and 0.0370 vs. 0.0243) and lower doses in spleen (1.4470 vs. 1.7693), respectively. Blood clearance of ¹⁷⁷Lu-DOTA-EB-TATE was also slower than ¹⁷⁷Lu-DOTATATE. For the tumors, ¹⁷⁷Lu-DOTA-EB-TATE had almost 4-fold higher residence time than ¹⁷⁷Lu-DOTATATE. Conclusion: This first-in-human study demonstrated the safety, dosimetry profile and provides first clinical evidence of the feasibility of SSTR-targeted somatostatin analogue ¹⁷⁷Lu-DOTA-EB-TATE. Based on its in vivo reversible albumin binding and controlled-release pharmacokinetics, ¹⁷⁷Lu-DOTA-EB-TATE exhibited higher tumor uptake with longer tumor residence time and remarkably improved tumor AUCs compared with ¹⁷⁷Lu-DOTATATE. Studies of therapeutic doses and treatment efficacy as compared to ¹⁷⁷Lu-DOTATATE is currently ongoing.

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