Preclinical pharmacokinetics, biodistribution, radiation dosimetry and toxicity studies required for regulatory approval of a phase I clinical trial with 111In-CP04 in medullary thyroid carcinoma patients

Abstract

IntroductionFrom a series of radiolabelled cholecystokinin (CCK) and gastrin analogues, 111In-CP04 (111In-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) was selected for further translation as a diagnostic radiopharmaceutical towards a first-in-man study in patients with medullary thyroid carcinoma (MTC). A freeze-dried kit formulation for multicentre application has been developed. We herein report on biosafety, in vivo stability, biodistribution and dosimetry aspects of 111In-CP04 in animal models, essential for the regulatory approval of the clinical trial.Materials and methodsAcute and extended single dose toxicity of CP04 was tested in rodents, while the in vivo stability of 111In-CP04 was assessed by HPLC analysis of mouse blood samples. The biodistribution of 111In-CP04 prepared from a freeze-dried kit was studied in SCID mice bearing double A431-CCK2R(±) xenografts at 1, 4 and 24 h pi. Further 4-h animal groups were either additionally treated with the plasma expander gelofusine or injected with 111In-CP04 prepared by wet-labelling. Pharmacokinetics in healthy mice included the 30 min, 1, 4, 24, 48 and 72 h time points pi. Dosimetric calculations were based on extrapolation of mice data to humans adopting two scaling models.ResultsCP04 was well-tolerated by both mice and rats, with an LD50 > 178.5 μg/kg body weight for mice and a NOAEL (no-observed-adverse-effect-level) of 89 μg/kg body weight for rats. After labelling, 111In-CP04 remained >70% intact in peripheral mouse blood at 5 min pi. The uptake of 111In-CP04 prepared from the freeze-dried kit and by wet-labelling were comparable in the A431-CCK2R(+)-xenografts (9.24 ± 1.35%ID/g and 8.49 ± 0.39%ID/g, respectively; P > 0.05). Gelofusine-treated mice exhibited significantly reduced kidneys values (1.69 ± 0.15%ID/g vs. 5.55 ± 0.94%ID/g in controls, P < 0.001). Dosimetry data revealed very comparable effective tumour doses for the two scaling models applied, of 0.045 and 0.044 mSv/MBq.ConclusionThe present study has provided convincing toxicology, biodistribution and dosimetry data for prompt implementation of the freeze-dried kit formulation without or with gelofusine administration in a multicentre clinical trial in MTC patients.

Clinical translation of theranostic radiopharmaceuticals: Current regulatory status and recent examples

“…This included pharmacology, toxicology, and dosimetry data that had to be retrieved from preclinical studies in vitro and in suitable animal models, which were summarized recently. 28 The binding affinity of CP04 and 111/nat In-CP04 for the CCK 2 R and the in vitro metabolic stability of 111 In-CP04 were previously reported. 29,30 New experiments in healthy mice revealed a fair in vivo metabolic stability of 111 In-CP04, and data was included in the IMPD.…”

“…Safety and efficacy information was also required to generate a suitable IMPD file for 111 In‐CP04 to submit the Clinical Trials. This included pharmacology, toxicology, and dosimetry data that had to be retrieved from preclinical studies in vitro and in suitable animal models, which were summarized recently …”

“…Such data were retrieved and included in the IMPD based on biodistribution data of 111 In‐CP04 in healthy mice for a 30‐min to 72‐h period post injection, showing the highest absorbed doses for kidneys. By employing two different dosimetric scaling options to translate mouse data to the human situation, almost identical values were obtained . The effective activity dose predicted for 111 In‐CP04 in the clinical trial was less than 10 mSv (9.9 mSv/220 MBq), well below that of the licensed product OctreoScan in SST2R imaging with SPECT (effective dose of 26 mSv/220 MBq according to SPC).…”

New Developments in Peptide Receptor Radionuclide Therapy

“…PRRT with radiolabeled gastrin analogs is therefore an attractive treatment option for patients with recurrent or metastatic medullary thyroid cancer. Of large libraries, the analogs 177 Lu-PP-F11N (Table 2) and 111 In-CP04 (PP-F11, Table 2), as a surrogate for 177 Lu-or 90 Y-labeled CP04, are currently in early prospective trials (LUMED/ NCT02088645 and GRAN-T-MTC/NCT03246659, respectively) to determine safety, maximum tolerated dose, biodistribution, and dosimetry (24,25). Preliminary clinical data identified the stomach as a potential dose-limiting organ, whereas the renal absorbed dose was rather low.…”

NEN — the role of somatostatin receptor scintigraphy in clinical setting

“…11 C-5-HTP (hydroxytryptophan) have shown promising results in detection of NENs, but further studies are necessary to confirm its utility [45]. Medullary thyroid cancer has an ability to take up gastrin and CCK-2 analogs which can be potential tools for diagnostic approach in that malignancy [46,47].…”