MITIGATE-NeoBOMB1, a Phase I/IIa Study to Evaluate Safety, Pharmacokinetics, and Preliminary Imaging of ⁶⁸Ga-NeoBOMB1, a Gastrin-Releasing Peptide Receptor Antagonist, in GIST Patients

Abstract

Introduction: Gastrin Releasing peptide receptors (GRPRs) are potential molecular imaging targets in a variety of tumors. Recently, a 68 Ga-labelled antagonist to GRPRs, NeoBOMB1, was developed for PET. We report on the outcome of a Phase I/IIa clinical trial (EudraCT 2016-002053-38) within the EU-FP7 project Closed-loop Molecular Environment for Minimally Invasive Treatment of Patients with Metastatic Gastrointestinal Stromal Tumours ('MITIGATE') (grant agreement number 602306) in patients with oligometastatic gastrointestinal stromal tumors (GIST). Materials and methods:The main objectives were evaluation of safety, biodistribution, dosimetry and preliminary tumor targeting of 68 Ga-NeoBOMB1 in patients with advanced TKI-treated GIST using PET/CT. Six patients with histologically confirmed GIST and unresectable primary or metastases undergoing an extended protocol for detailed pharmacokinetic analysis were included. 68 Ga-NeoBOMB1 was prepared using a kit procedure with a licensed 68 Ge/ 68 Ga generator. 3 MBq/kg body-weight were injected intravenously and safety parameters were assessed. PET/CT included dynamic imaging at 5 min, 11 min and 19 min as well as static imaging at 1, 2 and 3-4 h p.i. for dosimetry calculations. Venous blood samples and urine were collected for pharmacokinetics. Tumor targeting was assessed on a per-lesion and perpatient basis.Results: 68 Ga-NeoBOMB1 (50 µg) was prepared with high radiochemical purity (yield >97%). Patients received 174 ± 28 MBq of the radiotracer, which was well tolerated in all patients over a follow-up period of 4 weeks. Dosimetry calculations revealed a mean adsorbed effective dose of 0.029 ± 0.06 mSv/MBq with highest organ dose to the pancreas (0.274 ± 0.099 mSv/MBq). Mean plasma half-life was 27.3 min with primarily renal clearance (mean 25.7 ± 5.4% of injected dose 4h p.i.). Plasma metabolite analyses revealed high stability, metabolites were only detected in the urine. In three patients a significant uptake with increasing maximum standard uptake values (SUVmax at 2h p.i.: 4.3 to 25.9) over time was found in tumor lesions. Conclusion:This Phase I/IIa study provides safety data for 68 Ga-NeoBOMB1, a promising radiopharmaceutical for targeting GRPR-expressing tumors. Safety profiles and pharmacokinetics are suitable for PET imaging and absorbed dose estimates are comparable to other 68 Ga-labelled radiopharmaceuticals used in clinical routine.

In Vivo Biodistribution and Efficacy Evaluation of NeoB, a Radiotracer Targeted to GRPR, in Mice Bearing Gastrointestinal Stromal Tumor

“…[ 68 Ga]Ga-NeoB strongly visualized the prostate primary tumor but also metastatic foci such as liver and bone metastases, with high lesion to background ratio [ 24 ]. Furthermore, a recent Phase I/IIa clinical study was concluded assessing the safety, tolerability, pharmacokinetics and dosimetry of [ 68 Ga]Ga-NeoB in GIST patients (MITIGATE clinical trial, NCT02931929) [ 33 ]. Another important pre-clinical finding was the fact that the injected mass of NeoB constitutes a key parameter since it impacts the retention in off-target organs and therefore the dosimetry.…”

GMP-compliant production of [68Ga]Ga-NeoB for positron emission tomography imaging of patients with gastrointestinal stromal tumor

“…It could be suggested, that endoradiotherapy with [ 177 Lu]Lu/[ 225 Ac]Ac-NeoB would be an additional, more specific therapeutic option to SIRT, IRE or MWA in patients with high GRPR-expressing lesions in multiple organs. However, it should be taken into account that if tumorous lesions known from morphologic imaging do not show a [ 68 Ga]Ga-NeoB uptake, this might also be related to low GRPR expression (Gruber et al, 2020). It is well known that GIST have a wide spectrum of mutations, some of it with very low incidence (Lasota et al, 2006).…”

“…In preclinical studies the labeling method for [ 68 Ga]Ga-NeoB proved to be high yielding and stable (Pretze et al, 2021;Lau et al, 2019). As known from the first clinical study, [ 68 Ga]Ga-NeoB might have significant impact on the detection and treatment of GRPR expressing tumors such as like GIST (Gruber et al, 2020). Labeled with therapeutic radionuclides the peptide NeoB could also be useful for the treatment of imatinib-resistant GIST (Baratto et al, 2020).…”

­­­­GMP-conform production of [ 68Ga ]Ga-NeoB for positron emission tomography imaging of patients with gastrointestinal stromal tumor

“…showing no [ 68 Ga]Ga-NeoB uptake after SIRT therapy. The reason for the higher uptake in segment II/III could be a possible increased GRPR expression in growing GIST lesions or in metabolic active phases [29]. [29].…”