Abstract 676: First in man microdose trial of [68Ga]Ga-R54, CXCR4 targeted PET tracer: Comparison with [18F]-FDG and proof of concept in lung cancer models

Abstract CXCR4 is overexpressed on the majority of haematological and solid cancers and correlates with metastatic features. CXCR4 is a potential imaging target for the accuracy of diagnosis, staging and predictive treatment efficacy. Despite the development of CXCR4 targeting PET tracers, the sensitivity and specificity toward solid tumors is modest. A new CXCR4-targeting PET tracer, [68Ga]Ga-R54 (PCT/EP2020/087792) specifically accumulated in CXCR4-overexpressing tumors in in vivo murine models. Aim of the work is to extend the in vivo specificity and imaging efficacy of [68Ga]Ga-R54 in lung cancer and to evaluate the [68Ga]Ga-R54 in humans. Thus, PET/CT imaging and biodistribution was conducted on athymic mice bearing subcutaneous NCI-H69 (SCLC) and H460 (NSCLC) tumors. Biodistribution studies revealed high and specific tumour uptake in both H69 and H460 tumors s after 1 hour post injection (H69-tumor uptake: 12.2±1%ID/g; H460-tumor uptake: 2±0.4%ID/g) and rapid renal excretion. Competition with cold R54 reduced [68Ga]Ga-R54 uptake by approximately 90% and 60% respectively showing CXCR4 specificity. Compared to [18F]-FDG, [68Ga]Ga-R54 showed significantly higher uptake in H69 tumors (12.2±1%ID/g vs 3.75±0.6%ID/g, p<0.001). Consistently, PET/CT scans clearly visualized tumors at 1 hour post tracer administration with significant reduction in accumulation due to cold R54. Accordingly, high CXCR4 expression was revealed in H69 human lung cancer cells. Thus, a Microdose clinical study (ICH M3(R2) CPMP/ICH/286/95 Chapter 7.1) was planned to identify Pharmacokinetics/ Pharmacodynamic properties of [68Ga]Ga-R54 in metastatic/ advanced solid tumors. Toxicity and toxicokinetic as GLP-Extended single dose toxicity study in rats demonstrated non-evident toxicity induced by iv injection of 1000x the supposed clinical dose of [68Ga]Ga-R54 at 2 and 14 days post-injection. A monocentric, nonrandomized, open label clinical trial with [68Ga]Ga-R54 (R4-FOUR-PET - EU CT: 2024-513303-14-00) was recently approved on October 2024. R4-FOUR-PET will enrol 5 to 10 patients carrying CXCR4 expressing advanced cancers (breast, colon, lung, pancreas and ovarian) and will be conducted at the Nuclear Medicine of IRCCS-Pascale. Primary objective of the study is to evaluate pharmacokinetics and pharmacodynamics of a single microdose (<100μg) of [68Ga]Ga-R54; comparison with [18F]-FDG and correlation between SUVmax and CXCR4 IHC expression will be conducted. Patient’s enrolment is ongoing. Citation Format: Anna Maria Trotta, Luigi Portella, Michela Aurilio, Crescenzo D'Alterio, Francesco Manna, Costantina Maisto, Antonio Luciano, Giuseppe Palma, Gaetana Di Maiolo, Laura D'Ambrosio, Francesca Bruzzese, Roberta De Marino, Aureliana Esposito, Luigi Di Caterino, Valentina Vozza, Elena Sinopoli, Gianfranco De Feo, Francesco Perrone, Salvatore Di Maro, Secondo Lastoria, Stefania Scala. First in man microdose trial of [68Ga]Ga-R54, CXCR4 targeted PET tracer: Comparison with [18F]-FDG and proof of concept in lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 676.