Background: Conventional tools (eg, CT, MRI, biopsy) have limitations for characterizing renal mass histology; approx. 25% of patients with an indeterminant renal masses (IDRM) <4cm undergo surgery for benign disease. Accurate noninvasive techniques to risk stratify the IDRM remains an unmet need. Girentuximab is a monoclonal antibody that targets carbonic anhydrase IX (CAIX), an enzyme highly expressed in clear cell renal carcinoma (ccRCC). Radiolabeled ⁸⁹Zr-DFO-girentuximab is highly specific for CAIX and can aid differentiation between ccRCCs and other renal lesions. ZIRCON evaluated the performance of ⁸⁹Zr-DFO-girentuximab PET/CT for detection of ccRCC. Methods: In this open label, multicenter trial, patients with an IDRM (≤7cm; cT1) who were scheduled for partial nephrectomy within 90 days from planned ⁸⁹Zr-DFO-girentuximab administration were eligible. Enrolled patients received a single dose IV (37 MBq±10%; 10mg girentuximab) on Day 0 and underwent PET/CT imaging on Day 5 (±2d). Blinded central histology review determined ccRCC status. The co-primary objectives were to evaluate both the sensitivity and specificity of ⁸⁹Zr-DFO-girentuximab PET/CT imaging in detecting ccRCC in patients with IDRM, using histology as the standard of truth. Key secondary objectives included sensitivity and specificity of TLX250-CDx PET/CT imaging in the subgroup of patients with IDRM ≤4cm (cT1a). Other secondary objectives included positive and negative predictive values, and evaluation of safety and tolerability. The Wilson 95% confidence intervals (CI) lower bound for sensitivity and specificity had to be >70% and 68% respectively for ≥2 independent readers to declare the study successful. Results: 300 patients received ⁸⁹Zr-DFO-girentuximab (mean age, 62±12y; 71% Male). Of 288 patients with central histopathology of surgical samples, 193 (67%) had ccRCC, and 179 (62%) had cT1a. Of 284 evaluable patients, the average across all 3 readers for sensitivity and specificity was 86% [80%, 90%] and 87% [79%, 92%] resp. for coprimary, and 85% [77%, 91%] and 90% [79%, 95%] resp. for key secondary endpoints. For all evaluable patients, positive and negative predictive values were ≥ 91.7% and ≥ 73.7%, resp. PET+ ccRCC had higher mean CAIX expression compared with PET- ccRCC patients (p<0.05). Sensitivity and specificity were consistent with masses ≤2cm (n=46) of which, 26 were ccRCC+, 13 ccRCC−, and 3 unevaluable at central histopathology. Of 263 adverse events (AEs) in 124 patients, 2 AEs of mild intensity were treatment related. Conclusions: ZIRCON study confirms ⁸⁹Zr-DFO-girentuximab PET/CT is a well-tolerated and accurate modality for noninvasive identification of ccRCC in IDRM. This tool could be included in the diagnosis/management of patients with IDRM, limiting unnecessary treatment of benign lesions. Clinical trial information: NCT03849118.