87 First-in-Human Study of [111In] XYIMSR-01 SPECT/CT, a Novel Carbonic Anhydrase IX Small Molecule in Patients with Metastatic Clear Cell Renal Cell Carcinoma

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Abstract Background Clear cell renal cell carcinoma (ccRCC) accounts for approximately 75% of renal cancers and is characterized by von Hippel–Lindau (VHL) inactivation and subsequent upregulation of hypoxia-inducible factor-2α (HIF-2α), leading to overexpression of carbonic anhydrase IX (CAIX) in over 95% of tumors. CAIX represents an attractive theranostic target for molecular imaging and radioligand therapy. XYIMSR-01 is a novel low-molecular-weight CAIX-targeted molecule engineered for rapid clearance, high tumor to background contrast, and potential same-day imaging. Preclinical studies demonstrated strong tumor uptake, favorable biodistribution, and selective retention in CAIX-expressing ccRCC xenografts, supporting clinical translation. Based on these findings, a first-in-human study of indium-111 labeled XYIMSR-01 using single photon emission computed tomography (SPECT/CT) imaging has been initiated in patients with metastatic ccRCC. Methods This is an investigator-initiated, single-center, phase I study conducted at the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, designed to evaluate the safety, tolerability, and feasibility of [111In]XYIMSR-01 SPECT/CT imaging in patients with metastatic ccRCC. Eligible patients must have histologically confirmed ccRCC, ≥2 measurable metastatic lesions (size of each lesion at least ≥1.5 cm), treatment naïve, and have adequate organ and marrow function. Following informed consent, patients receive a single intravenous injection of 10.5 ± 1 mCi of [111In]XYIMSR-01, followed by whole-body planar and regional SPECT/CT imaging at 2-4, 24 ± 1, and 48 ± 1 hours post-injection. Blood samples are collected at multiple time points up to 48 hours to assess pharmacokinetics, clearance, and metabolic profile. Radiation dosimetry is calculated from serial imaging to estimate absorbed doses to tumor and normal organs. The primary objective is to assess the safety, tolerability, and feasibility of imaging with [111In]XYIMSR-01. Secondary objectives include characterization of biodistribution, radiation dosimetry, and pharmacokinetics. Exploratory analyses will evaluate concordance between [111In]XYIMSR-01 SPECT/CT with standard CT or MRI for lesion detection. The planned sample size is up to 10 patients. Successful completion of the study may support the development of future CAIX-targeted theranostic strategies in ccRCC. Clinical trial information (NCT07062549) Results N/A Conclusions N/A

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