Phase 1 Study of [ ¹⁷⁷ Lu]Lu-NeoB in Patients with Advanced Solid Tumors Overexpressing Gastrin-Releasing Peptide Receptor: Preliminary Safety and Dosimetry Results

Gastrin-releasing peptide receptor (GRPR) is overexpressed in a range of tumor types, making it an attractive candidate for novel treatment approaches. NeoB binds to GRPR with high affinity and can be radiolabeled with ⁶⁸Ga ([⁶⁸Ga]Ga-NeoB) for imaging or ¹⁷⁷Lu ([¹⁷⁷Lu]Lu-NeoB, hereafter ¹⁷⁷Lu-NeoB) for therapy, making it suitable for theranostics. <b>Methods:</b> NeoRay is a prospective, phase 1/2a, open-label, multicenter, first-in-human study of ¹⁷⁷Lu-NeoB. Patients with selected advanced solid tumors with GRPR expression (confirmed by [⁶⁸Ga]Ga-NeoB lesion uptake) were enrolled. Here, we report preliminary data (cutoff, April 29, 2024) from phase 1, which aimed to identify the maximum tolerated dose and/or recommended phase 2 dose of ¹⁷⁷Lu-NeoB. Patients were scheduled to receive at least 3 cycles of ¹⁷⁷Lu-NeoB at an interval of at least 6 wk. A Bayesian optimal interval design was used, with dose-escalation decisions based on dose-limiting toxicities (DLTs) during cycle 1 of each dose level. The primary endpoint was the incidence and nature of DLTs. Safety was assessed before and throughout each cycle. Dosimetry was assessed after the first administration. <b>Results:</b> Seventeen patients (median age, 65 y; 71% male) with advanced gastrointestinal stromal tumors, prostate cancer, glioblastoma, or breast cancer received ¹⁷⁷Lu-NeoB activities of 1.85 GBq (cycle 1) and then 5.55 GBq (cycles 2-4) (<i>n</i> = 3), 9.25 GBq (<i>n</i> = 9), or 11.1 GBq (<i>n</i> = 5). Four DLTs were observed in 3 patients who received 11.1 GBq: grade 3 anemia (<i>n</i> = 2), grade 4 neurologic decline (<i>n</i> = 1), and grade 3 encephalopathy (<i>n</i> = 1). No DLTs were observed at lower administered activities. Overall, 4 of 17 patients (23.5%) had treatment-related adverse events of grade 3 or higher. Among patients with at least 1 evaluable dosimetry measurement (<i>n</i> = 16), the mean absorbed dose coefficient was 0.10 Gy/GBq (SD, 0.056 Gy/GBq) in the kidneys, 0.055 Gy/GBq (SD, 0.039 Gy/GBq) in the pancreas, and 0.018 Gy/GBq (SD, 0.0076 Gy/GBq) in the red marrow. <b>Conclusion:</b> ¹⁷⁷Lu-NeoB has a favorable organ dosimetry profile in patients with advanced solid tumors expressing GRPR, with a large safety margin compared with accepted external beam radiation therapy thresholds for organ toxicity. The maximum tolerated dose of ¹⁷⁷Lu-NeoB was identified as 9.25 GBq, and the recommended phase 2 dose for the phase 2a dose expansion is 9.25 GBq.