Title: Phase I clinical trial using a novel CCK-2/gastrin receptor-localizing radiolabelled peptide probe for personalized diagnosis and therapy of patiens with progressive or metastatic medullary thyroid carcinoma.

Project Coordinator:
Alicja HUBALEWSKA-DYDEJCZYK (Poland) Jagiellonian University Medical College, Department of Endocrinology

Project Partners:
Paola Anna ERBA (Italy) Azienda Ospedaliero-Universitaria Pisana, Nuclear Medicine Regional Center, Pisa
Clemens DECRISTOFORO (Austria) Innsbruck Medical University, Department of Nuclear Medicine, Innsbruck
Helmut MAECKE (Germany) University Hospital Freiburg, Department of Nuclear Medicine, Freiburg
Theodosia MAINA (Greece) IRRP, NCSR “Demokritos”, Molecular Radiopharmacy, Athens
Renata MIKOLAJCZAK (Poland) National Centre For Nuclear Research, Radioisotope Centre POLATOM, Otwock
Katja ZALETEL (Slovenia) University Medical Centre Ljubljana, Department of Nuclear Medicine, Ljubljana

Project Abstract:
Medullary thyroid carcinoma (MTC) is still one of the most challenging cancers for both physicians and patients. Therefore, it is necessary to develop alternative therapeutic strategies to control tumour growth, possibly through the use of new biomarkers. The cholecystokinin 2 (CCK-2) receptor is overexpressed in MTC with very high density and incidence of over 90%, as revealed by autoradiographic studies. From the late 1990’s, a variety of CCK-2/gastrin related peptides (members of the gastrin- and cholecystokinin families, or possessing characteristics of both), were studied in vitro and in preclinical animal models. In a comparison performed within COST BM0607 the DOTA-DGlu-DGlu-DGlu-DGlu-DGlu-DGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 (CP04) showed most promising characteristics in terms of high stability and receptor affinity, high and persistent tumour uptake and low kidney retention and therefore was selected for further clinical evaluation. The aim of the project is to establish the multinational cooperation in the innovative field of targeted radionuclide therapy using a CCK-2/gastrin receptor-seeking ligand CP04 radiolabelled with Indium-111 as imaging biomarker. The project will correlate the work of partners from Austria, Greece, Poland, Italy, Slovenia and Germany. CCK-2/gastrin receptors may become viable targets for radionuclide scintigraphy and radionuclide therapy, similarly to somatostatin receptors which were instrumental to establish nuclear medicine efficacy in clinical practice.

Publishable Summary:
The project aimed to develop a novel biomarker for advanced medullary thyroid cancer (MTC) and subsequent therapy on the basis of overexpression of CCK2 receptor in MCT. The justification of the search for this new approach to MTC diagnosis and therapy is the limited efficacy of available treatment options even when tyrosine kinase inhibitors are used.
The project was a phase I study with 111In-labelled gastrin analogue (DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 (CP04) which had been selected as a candidate for innovative MTC therapy because of a very high CCK2 receptor expression in MTC and its best pharmacokinetics properties among several gastrin analogues tested. The study design comprised 2 phases: a preclinical part (radiopharmaceutical development) and a clinical trial. Within the first phase, and in accordance with GMP, stability, radiolabelling, and toxic­ity of 111In‑CP04 were tested enabling the initiation of a clinical study in humans. The main objective of the clinical part was to establish the safety of i.v. administration of 111In-CP04, to assess the tracer biodistribution and dosimetry in MTC lesions and in normal tissues, and to establish the ability of the biomarker to visualize cancer tissue.
In phase 1A of the clinical trial, two peptide amounts, both radiolabelled with 111In (200 +/– 10% MBq), were administered: a low amount (10 μg) was used as a safety step in the first applications of CP04 and 50 μg, an amount also suitable for therapy, was applied. After safety assurance, in phase 1B, only the 50 μg of 111In‑CP04 was applied and enrolled patients were randomized to arm 1 or 2 with or without coadministration of gelofusine (a nephroprotec­tive agent).
The study confirmed that the novel biomarker 111In-CP04 is safe after intravenous injection and that MTC tissue can be visualized by 111In-CP04 with high sensitivity. Biodistribution and dosimetry data showed CP04 as a promising radiopharmaceutical for therapy of advanced MTC if labelled with the therapeutic radioisotope 177Lu.

(Project funded under JTC 2011)