Abstract CT178: A phase 1/2, open-label study to assess safety, tolerability, biodistribution, radiation dosimetry and PET imaging characteristics of [18F]FPyGal in comparison to in-vitro diagnostic for the assessment of senescence in oncological patients
Authors: LaFougere Christian , Gueckel Brigitte , Dittmann Helmut , Hinterleitner Martina , Trautwein Nils , Cotton Jonathan , Kienzle Gabriele , Singer Stephan , Reischl Gerald , Lauer Ulrich , Pichler Bernd , Zender Lars 
Published: June 2022

Abstract
It is well established that senescence of cancer cells can be induced by treatment with classical cytotoxic therapies but also by molecularly targeted therapies or immunotherapies, a phenomenon referred to as therapy induced senescence (TIS). Occurrence of intratumoral senescence harbors broad therapeutic implications and may limit the prognosis of cancer patients, as senescent cells, via their senescence associated secretory phenotype (SASP), can suppress anti-tumour immune responses and may increase the metastatic potential of non-senescent cancer cells. Preclinical data suggest that an eradication of senescent cells (senolytic therapies) or an application of SASP modulating therapies might improve the outcome of systemic cancer therapies, however, as a prerequisite to guide such approaches, robust and non-invasive modalities to visualize and quantify intratumoral senescence are needed.
Here we report on the preclinical and clinical development of the novel Positron-Emission-Tomography (PET) tracer [18F]FPyGal, a radiolabeled substrate of senescence-associated ꞵ-galactosidase. After thorough preclinical characterization of [18F]FPyGal in mouse models of TIS, we conducted a phase I study (NCT04536454) to assess i) safety and tolerability of [18F]FPyGal (primary endpoints) and ii) to characterize dosimetry and pharmacokinetics (secondary endpoints) as well as possible regions of physiologically increased tracer uptake after i.v. injection of [18F]FPyGal (mean 372.5±9.6) MBq in eight male healthy volunteers (mean 35.0±9.6 y; range 26-53 y). No treatment related adverse events (trAEs) or severe adverse events (SAEs) were recorded. No abnormal findings or changes were noted on physical examinations, vital signs and pulse oximetry values. Except for a transient reduction in leukocyte and neutrophil counts (6 h p.i.) in one patient (12.5%), no other abnormal laboratory values were observed. The total body absorbed dose was 4.40±0.08 μGy/MBq, highest mean absorbed doses were found in the urinary bladder wall (81.55±1.06 μGy/MBq), kidneys (21.05±4.74 μGy/MBq) and heart wall (9.77±1.32 μGy/MBq). The normalized whole-body effective radiation dose was 8.09±0.17 μSv/MBq. Collectively, our data show that i) [18F]FPyGal can robustly detect intratumoral senescence in preclinical cancer mouse models and ii) that the use of [18F]FPyGal was safe and well-tolerated in the described human study population. Radiation exposure was low and comparable to other clinically available 18F-labelled PET-tracers. In a second stage of our phase I trial, we are currently correlating [18F]FPyGal PET signals with histopathological senescence markers in human cancer patients.
Citation Format: Christian LaFougere, Brigitte Gueckel, Helmut Dittmann, Martina Hinterleitner, Nils Trautwein, Jonathan Cotton, Gabriele Kienzle, Stephan Singer, Gerald Reischl, Ulrich Lauer, Bernd Pichler, Lars Zender. A phase 1/2, open-label study to assess safety, tolerability, biodistribution, radiation dosimetry and PET imaging characteristics of [18F]FPyGal in comparison to in-vitro diagnostic for the assessment of senescence in oncological patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT178.