[111In]In-CP04 as a novel cholecystokinin-2 receptor ligand with theranostic potential in patients with progressive or metastatic medullary thyroid cancer: final results of a GRAN-T-MTC Phase I clinical trial

Luka Lezaic, Paola Anna Erba, Clemens Decristoforo, Katja Zaletel, Renata Mikolajczak, Helmut Maecke, Theodosia Maina, Mark Konijnenberg, Petra Kolenc, Malgorzata Trofimiuk-Müldner, Elwira Przybylik-Mazurek, Irene Virgolini, Marion de Jong, Alide C. Fröberg, Christine Rangger, Gianpaolo Di Santo, Konrad Skorkiewicz, Piotr Garnuszek, Bogdan Solnica, Berthold A. NockDanuta Fedak, Paulina Gaweda, Alicja Hubalewska-Dydejczyk*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Introduction: Medullary thyroid cancer (MTC) is a rare malignant tumour of the parafollicular C-cells with an unpredictable clinical course and currently suboptimal diagnostic and therapeutic options, in particular in advanced disease. Overexpression of cholecystokinin-2 receptors (CCK2R) represents a promising avenue to diagnostic imaging and targeted therapy, ideally through a theranostic approach. Materials and methods: A translational study (GRAN-T-MTC) conducted through a Phase I multicentre clinical trial of the indium-111 labelled CP04 ([111In]In-CP04), a CCK2R-seeking ligand was initiated with the goal of developing a theranostic compound. Patients with proven advanced/metastatic MTC or short calcitonin doubling time were enrolled. A two-step concept was developed through the use of low- and high-peptide mass (10 and 50 μg, respectively) for safety assessment, with the higher peptide mass considered appropriate for therapeutic application. Gelofusine was co-infused in a randomized fashion in the second step for the evaluation of potential reduction of the absorbed dose to the kidneys. Imaging for the purpose of biodistribution, dosimetry evaluation, and diagnostic assessment were performed as well as pre-, peri-, and postprocedural clinical and biochemical assessment. Results: Sixteen patients were enrolled. No serious adverse events after application of the compound at both peptide amounts were witnessed; transient tachycardia and flushing were observed in two patients. No changes in biochemistry and clinical status were observed on follow-up. Preliminary dosimetry assessment revealed the highest dose to urinary bladder, followed by the kidneys and stomach wall. The effective dose for 200 MBq of [111In]In-CP04 was estimated at 7±3 mSv and 7±1 mSv for 10 μg and 50 μg CP04, respectively. Administration of Gelofusine reduced the dose to the kidneys by 53%, resulting in the organ absorbed dose of 0.044±0.019 mSv/MBq. Projected absorbed dose to the kidneys with the use of [177Lu]Lu-CP04 was estimated at 0.9±0.4 Gy/7.4 GBq. [111In]In-CP04 scintigraphy was positive in 13 patients (detection rate of 81%) with superior diagnostic performance over conventional imaging. Conclusion: In the present study, [111In]In-CP04 was shown to be a safe and effective radiopharmaceutical with promising theranostic characteristics for patients with advanced MTC.

Original languageEnglish
Pages (from-to)892-907
Number of pages16
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Volume50
Issue number3
Early online date5 Nov 2022
DOIs
Publication statusPublished - Feb 2023

Bibliographical note

Funding Information:
GRAN-T-MTC was a part of the ERA-NET on Translational Cancer Research (TRANSCAN) First Joint Transnational Call for Proposals 2011 (JTC 2011) on: “Validation of biomarkers for personalised cancer medicine” funded by the European Commission under the Seventh Framework Programme (FP7); Trial registration EUDRA-CT number: 2015-000805-38, with the following national co-found institutions: Ministry of Health (MoH), Italy, National Centre for Research and Development (NCBiR), Poland, Federal Ministry of Education and Research (BMBF), Germany, Austrian Science Fund (FWF), Austria, Ministry of Education, Science and Sport, Slovenia (MIZS), General Secretariat for Research and Technology, Ministry of Education, Life Long Learning and Religious Affairs (GSRT), Greece.

Publisher Copyright:
© 2022, The Author(s).

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