Next-Generation Peptide Receptor Radionuclide Therapy: A Phase 1 Dose-Escalation and Dosimetry Study of...

Neuroendocrine tumors (NETs) are often detected late, limiting curative treatments and requiring systemic therapies such as peptide receptor radionuclide therapy (PRRT). Although ¹⁷⁷Lu-DOTATATE has demonstrated efficacy, its rapid clearance from the circulation limits tumor radiation delivery and may increase renal toxicity risk. ¹⁷⁷Lu-DOTA-EB-TATE, a novel PRRT agent conjugated with Evans blue for albumin binding, offers extended circulation time and enhanced tumor uptake, potentially improving therapeutic outcomes. This phase 1 study aimed to evaluate the safety, dosimetry, and preliminary efficacy of ¹⁷⁷Lu-DOTA-EB-TATE in patients with advanced gastroenteropancreatic NETs. Methods: Six adults with inoperable, measurable gastroenteropancreatic NETs (WHO grades 2 and 3) and with somatostatin receptor overexpression were enrolled. Using a 3 + 3 dose-escalation design, patients received ¹⁷⁷Lu-DOTA-EB-TATE at nominal activities of 1.85, 3.70, or 5.55 GBq intravenously for 2 cycles, 6 wk apart. Individualized dosimetry after the first cycle informed subsequent treatment delivery. Safety was assessed biweekly, and tumor responses were evaluated using RECIST at 3 and 6 mo. Results: Treatment was well-tolerated, with mild side effects, including nausea, fatigue, and hair loss; no renal toxicity occurred. The median kidney absorbed dose per cycle was 4.8 Gy (range, 2.9-8.9 Gy; mean, 2.2 Gy/GBq). Hematologic toxicity was dose-limiting, with persistent grade 3 febrile neutropenia observed at 3.7 GBq in 1 patient and confirmed in an external cohort. Thus, the maximum tolerated activity was set at 3.70 GBq and the recommended phase 2 activity at 1.85 GBq per cycle to avoid irreversible marrow suppression. Tumor responses included stable disease (n = 5) and partial response (n = 1) at 3 mo; disease progressed in 2 patients at 6 mo after treatment completion. Conclusion: The 2-cycle regimen of ¹⁷⁷Lu-DOTA-EB-TATE delivered higher renal absorbed doses compared with standard ¹⁷⁷Lu-DOTATATE. With individualized dosimetry, no kidney toxicity was observed. However, increased retention in the circulation caused hematologic-related side effects and made marrow the dose-limiting organ. Within the defined dosing limits of this study, ¹⁷⁷Lu-DOTA-EB-TATE is a potential high-uptake alternative to standard PRRT, supporting a shortened 2-cycle schedule for earlier response assessment. Further research should refine dosing schedules and patient selection to balance efficacy and safety.