Cholecystokinin 2 Receptor Agonist 177Lu-PP-F11N for Radionuclide Therapy of Medullary Thyroid Carcinoma: Results of the Lumed Phase 0a Study

Abstract

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.

Keywords: 177Lu-PP-F11N; cholecystokinin 2 receptor targeting; peptide receptor radionuclide therapy; theranostics.

© 2020 by the Society of Nuclear Medicine and Molecular Imaging.

Figures

FIGURE 1.

177Lu-PP-F11N SPECT/CT scans in coronal orientation 24 h after injection. In all 6 patients (patients 1–6 [A–F, respectively]), several tumors were visualized with SPECT (white arrows). Minimal diameter of detectable tumor was 8 mm (patient 6 [F]). C = colon; S = stomach.

FIGURE 2.

Planar scans (anterior view) of patient 2 without and with coadministration of SG at 1, 4, 24, and 72 h after injection (p.i.) of 1 GBq of 177Lu-PP-F11N. On planar scans, 2 tumors with diameters of 10 × 10 mm and 7 × 18 mm (black arrows) were visible. B = urinary bladder; C = colon; K = kidneys; S = stomach; U = urine contamination.

FIGURE 3.

(A–D) Images from patient 3 showing axial 177Lu-PP-F11N SPECT/CT scan (A) of suspicious lymph node (red arrow), corresponding tissue stained with hematoxylin–eosin (B), and in vitro autoradiograms of adjacent sections indicating total binding of 111In-PP-F11N (C) and nonspecific binding (D). (E and F) Dog stomach tissue as positive control. Lesion (9 × 9 mm) with uptake on SPECT/CT scan (A) corresponds to lymph node metastasis with 60% tumor cells (B) and specific 111In-PP-F11N binding (C). Red bars = 10 mm. Additional series are shown in Supplemental Figure 1.