The purpose of this study is to identify changes in Carbonic Anhydrase IX (CAIX) expression induced by hypoxia-inducible factor 2 alpha (HIF-2α) inhibition by initiating belzutifan single agent therapy and imaging CAIX expression with 89Zr-DFO-girentuximab PET before and 4 weeks after initiating treatment. This will be the first study to evaluate potential changes in CAIX expression altered by belzutifan. Information gained from this study will be leveraged to develop combinations of belzutifan with CAIX targeted agents including radioimmunotherapy in the future.

Inclusion Criteria:

1. Histologically confirmed advanced clear cell RCC

2. Radiographic disease progression to prior immune checkpoint inhibitor (ICI) therapy for RCC

   • ICI for adjuvant therapy: Patients who experienced radiographic tumor progression during or within 6 months after last dose of adjuvant ICI
   • ICI for locally advanced or metastatic disease: radiographic disease progression during or following ICI treatment in the 1st line setting
   • Minimum two previous treatment regimens but no maximum limit

3. Measurable disease per RECIST v1.1

4. Recovery to baseline or Grade1 NCI CTCAE v5.0 from toxicities related to any prior treatments, unless adverse events are clinically nonsignificant and/or stable in the opinion of the investigator.

5. Age>18 years of age

6. Karnofsky performance score ≥60%

7. Patients must have adequate organ and marrow function as defined below:

   • absolute neutrophil count ≥1,000/mcL

   • platelets ≥100,000/mcL

   • total bilirubin ≤ institutional upper limit of normal (ULN)

   • Aspartate Aminotransferase (AST) (SGOT)/Alanine Aminotransferase (ALT) (SGPT ≤3 × institutional ULN

   • creatinine ≤ institutional ULN OR

   • glomerular filtration rate (GFR) ≥60 mL/min/1.73 m2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m2

     1. Patients with abnormal test results outside the allowable range, but are not clinically significant, may still enroll with PI's review and approval.
     2. Laboratory reference values should account for potential normal variations due to race, ethnicity, age, sex, and gender identity (e.g., due to surgical and/or hormonal changes).

8. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

9. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

10. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

11. Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.

12. Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy.

13. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

14. Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.

15. Patients who agree to use an adequate method of contraception throughout the study period, starting with the administration of 89Zr-DFO-girentuximab,

16. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1) with the exception of alopecia.
2. Patients who are receiving any other investigational agents.
3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to girentuximab.
4. Patients with uncontrolled intercurrent illness at the discretion of the investigator.
5. Pregnant women are excluded from this study because belzutifan is an agent with the potential for teratogenic or abortifacient effects.

As this is a single institutional trial, individual participant data (IPD) will not be shared. This study will comply with the NIH Public Access Policy, which ensures that the public has access to the published results of NIH funded research. It requires scientists to submit final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for publication.