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 is known that cholecystokinine-2 receptor (CCK2R) is a promising target for the treatment of MTC with radiolabeled minigastrin analogues. Unfortunately, kidney toxicity precluded their therapeutic application so far. In 6 consecutive patients we evaluated with advanced 3D dosimetry whether improved minigastrin analogue 177 Lu-DOTA-(DGlu) 6-Ala-Tyr-Gly-Trp-Nle-Asp-PheNH 2 (177 Lu-PP-F11N) is a suitable agent for the treatment of MTC. Methods: Patients received two injections of about 1 GBq (~80 µg) 177 Lu-PP-F11N with and without a solution of succinylated gelatin (SG, a plasma expander used for nephroprotection) in a random cross-over sequence in order to evaluate biodistribution, pharmacokinetics as well as tumor-and organ dosimetry. Electrocardiogram, blood count and blood chemistry were measured up to 12 weeks after administration of 177 Lu-PP-F11N to assess safety. Results: In all patients 177 Lu-PP-F11N accumulation was visible in tumor tissue, stomach and kidneys. Altogether 13 tumors were eligible for dosimetry. The median (interquartile range = IQR) absorbed dose for tumors, stomach, kidneys and bone marrow was 0.88 Gy/GBq (0.

Pharmacological inhibition of mTORC1 increases CCKBR-specific tumor uptake of radiolabeled minigastrin analogue [177Lu]Lu-PP-F11N

“…Notably, a previous study also suggested improvement of the tumor uptake by combinatory treatment, whereby co-administration of the neutral endopeptidase inhibitor phosphoramidon (PA) increased the level of circulating radiopeptides, including the gastrin analogue [ 111 In]In-DOTA-MG11, and remarkably enhanced tumor uptake in mouse models 54 . In contrast to our method, this combinatory strategy robustly increased uptake in the stomach, a dose-limiting organ for PRRT with radiolabeled minigastrin 22 , and did not affect tumor viability or radio-sensitivity, which additionally can increase therapeutic responses. In addition, mTORC1 inhibition can normalize tumor vessels and enhance delivery of chemotherapeutics such as paclitaxel as previously demonstrated in rapamycin-treated breast cancer mouse models 55 .…”

“…Furthermore, comparative biodistribution analysis in the mouse model shows that [ 177 Lu]Lu-PP-F11N reached a tumor uptake that other Lu-117-labeled mingastrin analogues could only achieve in combination with protease inhibitors indicating its high metabolic stability 21 . A more recent clinical study shows favorable biodistribution and pharmacokinetics of 177 Lu[Lu]-PP-F11N and low kidney radiation doses with a median tumor-to-kidney dose ratio of 11.6 22 . Nevertheless, in the latter study, radiolabeled minigastrin also accumulated in the stomach due to endogenous expression of the CCKBR and reached a tumor-to-stomach dose ratio of 3.34.…”

Initial In Vitro and In Vivo Evaluation of a Novel CCK2R Targeting Peptide Analog Labeled with Lutetium-177

“…The additional substitution with Pro did, however, not show a considerable effect on in vivo stability. Still, the in vivo stability of [ 177 Lu]Lu- 1 is highly improved when compared to other MG analogs which are currently investigated in clinical trials [ 22 , 24 ]. For PP-F11 labeled with indium-111, the metabolic stability in the blood of mice was tested for the time point of 5 min p.i.…”

“…Most of these developments have not led to the required improvements necessary for successful clinical application. Two MG analogs, DOTA-(DGlu) 6 -Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH 2 (PP-F11) labeled with indium-111 as well as DOTA-(DGlu) 6 -Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH 2 (PP-F11N) labeled with lutetium-177, which are derived from MG0 by inversion of the configuration of the penta-Glu motif, are currently examined in clinical studies ( Identifier: NCT03246659 and NCT02088645) [ 22 , 23 , 24 ]. Besides chemical modification of the peptide, in situ stabilization by co-injection of enzyme inhibitors was investigated.…”

The Association Between Lymph Node Stage and Clinical Prognosis in Thyroid Cancer

“…PTC and follicular thyroid cancer (FTC) are classified as differentiated TCs that both arise from thyroid follicular cells and generally have excellent prognoses, while the poorly differentiated thyroid cancers have a poorer prognosis which probably arises from either PTCs or FTCs. Medullary thyroid cancer (MTC) has been derived from the parafollicular C cells, accounting for about 1-2% of TCs (5). Anaplastic thyroid cancer (ATC) originates from follicular cells and is an aggressive, undifferentiated, and rapidly fatal tumor (6).…”