⁸⁹Zirconium-labelled girentuximab (⁸⁹Zr-TLX250) PET in Urothelial Cancer Patients (ZiPUP): protocol for a phase I trial of a novel staging modality for urothelial carcinoma

Abstract

IntroductionBladder cancer is a lethal disease with a rising incidence on a background of limited conventional imaging modalities for staging (either CT of the chest-abdomen-pelvis or 18F-fluorodeoxyglucose positron emitting tomography (FDG-PET/CT)). CT is known to have relatively low sensitivity for detecting low volume metastatic disease, an important goal when considering surgical interventions entailing significant potential morbidity. FDG is also limited, being predominantly renally excreted and, therefore, producing intense non-specific activity in the urinary tract, which limits its utility to detect bladder and upper tract lesions, or nodal metastases in close proximity to the urinary tract. 89Zirconium-labelled girentuximab (89Zr-TLX250) may have utility in the accurate staging of bladder and urothelial carcinomas, with less renal excretion as compared with FDG; however, this has not previously been investigated.Methods and analysis89Zirconium-labelled girentuximab PET in Urothelial Cancer Patients is a single-arm phase I trial examining the feasibility of using 89Zr-TLX250-PET/CT as a staging modality for urothelial and bladder carcinomas by examining isotope uptake by the cancer. This trial will also examine the safety and utility of 89Zr-TLX250-PET/CT in patients either undergoing preoperative staging of bladder or other urothelial carcinomas for curative intent, or with known metastatic urothelial carcinomas. All participants will undergo 89Zr-TLX250-PET/CT and will need to have undergone recent FDG-PET/CT for comparison. This trial aims to recruit 10 participants undergoing preoperative staging and 10 participants with known metastatic disease. The primary endpoint is feasibility defined by the ability to recruit to the target sample size within the study duration; secondary endpoints are safety, tolerability, sensitivity and specificity in detecting lymph node metastases compared with FDG-PET/CT.Ethics and disseminationEthics approval has been obtained from the South Metropolitan Health Service Human Research Ethics Committee (RGS0000003940). Eligible patients will only be enrolled after providing written informed consent. Patients will be given a full explanation, in lay terms, of the aims of the study and potential risks including as a written patient information sheet.Trial registration numbersACTRN12621000411842, NCT05046665.

Comparing fluorodeoxyglucose positron emission tomography with computed tomography in staging for nodal and distant metastasis in urothelial/bladder cancer

“…[16][17][18][19][20] Early phase evaluation of molecular targets in urothelial malignancy, such as carbonic anhydrase IX (radiolabelled girentuximab), allowing reagents that are hepatically cleared, is underway. 21 There have been limited reports comparing preoperative staging of bladder cancer with 18 F-FDG-PET and conventional CT. In a cohort of 300 patients, FDG-PET was more accurate than conventional CT staging alone for preoperative LN staging with a sensitivity of 40.3% compared with 13.4% for CT. 22 In our study, the sensitivity of both modalities was higher, although the sensitivity of CT remained relatively low, raising a major concern in relying solely on this for staging.…”

“…While urinary excretion of FDG limits assessment of local urinary tract lesions on PET, it is possible to augment imaging protocols with diuretics to permit urinary tract lesion assessment 16–20 . Early phase evaluation of molecular targets in urothelial malignancy, such as carbonic anhydrase IX (radiolabelled girentuximab), allowing reagents that are hepatically cleared, is underway 21 …”

“… 16 , 17 , 18 , 19 , 20 Early phase evaluation of molecular targets in urothelial malignancy, such as carbonic anhydrase IX (radiolabelled girentuximab), allowing reagents that are hepatically cleared, is underway. 21 …”

Current and potential roles of immuno-PET/-SPECT in CAR T-cell therapy

“…Therefore, recent CAR T-cell therapy strategies have been expanded to include transduction of the CAR design with hypoxia-sensing domains ( 257 ) and targeting of antigens upregulated in hypoxia [e.g., carbonic anhydrase IX (CAIX) ( 258 )] in order to improve the therapeutic efficacy ( 32 , 259 ). Of note, immuno-PET with 124 I or 89 Zr-labeled girentuximab, an anti-CAIX mAb, has advanced to clinical trials in patients with renal cell carcinoma ( 260 – 262 ) and urothelial cancers ( 263 ), while the 89 Zr-labeled mAb has demonstrated improved detection sensitivity due to the residualizing properties of the radionuclide ( 264 ). Immuno-PET/-SPECT with radiolabeled pH-selective mAbs, which has not yet been reported, might find application in non-invasive assessment of TME acidosis ( 265 ).…”