An Investigational Scan (89Zr-DFO-Girentuximab PET/CT) for Determining the Treatment Effects of Belzutifan in Patients with Advanced Clear Cell Renal Cell Cancer

Status: temporarily closed to accrual

This phase Ib trial studies the side effects of an investigational scan, 89Zr-DFO-girentuximab positron emission tomography/computed tomography (PET/CT), and evaluates how well it works in determining the effects of treatment with belzutifan in patients with clear cell renal cell cancer (ccRCC) that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Belzutifan, a new drug, was recently approved by the Food and Drug Administration (FDA) (2021), but it only works for a small group of patients. Belzutifan works by blocking HIF-2α, a protein that causes changes in how cells signal each other, which happens after a mutation (alteration) in the Von Hippel-Lindau (VHL) gene. The VHL gene helps to keep cell growth in check and ensures that the body doesn't grow abnormal blood vessels or tumors. This VHL mutation is the main cause of RCC tumors, because it monitors the balance of oxygen and stops certain proteins from building up in the body when there's too much oxygen, meaning it stabilizes hypoxia inducible factors (HIF-2α). This mutation then triggers the production of genes that help the tumor grow and spread. In lab tests, blocking a protein called HIF-2α makes another protein, HIF-1α, build up in tumor cells. This causes an increase in the amount of a protein called carbonic anhydrase IX (CAIX). Belzutifan may boost the activity of HIF-1, which will cause CAIX levels to go up. 89Zr-DFO-girentuximab PET/CT imaging is a type of scan that helps doctors see certain kidney cancers, like ccRCC, by looking for the CAIX protein. This imaging test can detect RCC, even in kidney masses that doctors aren’t sure about. The 89Zr-DFO-girentuximab PET/CT scans may be able to help doctors determine how to combine belzutifan with drugs that target the CAIX protein in the future.

Inclusion Criteria

Histologically confirmed advanced clear cell RCC
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
Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
Recovery to baseline or Grade 1 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 from toxicities related to any prior treatments, unless adverse events are clinically non-significant and/or stable in the opinion of the investigator
Age > 18 years of age
Karnofsky performance score ≥ 60%
Absolute neutrophil count ≥ 1,000/mcL * Patients with abnormal test results outside the allowable range, but are not clinically significant, may still enroll with principal investigator's (PI’s) review and approval * 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)
Platelets ≥ 100,000/mcL * Patients with abnormal test results outside the allowable range, but are not clinically significant, may still enroll with PI’s review and approval * 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)
Total bilirubin ≤ institutional upper limit of normal (ULN) * Patients with abnormal test results outside the allowable range, but are not clinically significant, may still enroll with PI’s review and approval * 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)
Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) ≤ 3 × institutional ULN * Patients with abnormal test results outside the allowable range, but are not clinically significant, may still enroll with PI’s review and approval * 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)
Creatinine ≤ institutional ULN OR glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m^2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2 * Patients with abnormal test results outside the allowable range, but are not clinically significant, may still enroll with PI’s review and approval * 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)
Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
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
Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression
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
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
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
Patients who agree to use an adequate method of contraception throughout the study period, starting with the administration of 89Zr-DFO-girentuximab
Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

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
Patients who are receiving any other investigational agents
History of allergic reactions attributed to compounds of similar chemical or biologic composition to girentuximab
Patients with uncontrolled intercurrent illness at the discretion of the investigator
Pregnant women are excluded from this study because belzutifan is an agent with the potential for teratogenic or abortifacient effects

PRIMARY OBJECTIVES:

I. To evaluate the change in zirconium Zr 89 girentuximab (89Zr-DFO-girentuximab) PET uptake (maximum standardized uptake value [SUV] max and SUV peak) in ccRCC lesions between baseline and 4 weeks after initiation of belzutifan treatment.

II. Safety and tolerability as measured by the incidence of adverse events (AEs), serious adverse events (SAEs), AEs leading to discontinuation, deaths, laboratory abnormalities and changes from baseline.

EXPLORATORY OBJECTIVES:

I. To evaluate the association between liquid next generation sequencing (NGS) findings and 89Zr-DFO-girentuximab PET SUV and CAIX tumor volumes (TCTV changes [qualitatively+ quantitatively]) between baseline and 4 weeks after belzutifan treatment.

II. To investigate the impact of belzutifan treatment on the RCC transcriptional profile, including the expression of HIF-1 and HIF-2, using single cell ribonucleic acid (RNA) sequencing on biopsy specimens obtained from first 10 patients at end of study period.

OUTLINE:

Patients receive belzutifan orally (QD) daily for 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive 89Zr-DFO-girentuximab intravenously (IV) and undergo PET scans 1-7 days before and 1-7 days after belzutifan treatment. Patients also undergo collection of blood samples and a biopsy on study.

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An Investigational Scan (89Zr-DFO-Girentuximab PET/CT) for Determining the Treatment Effects of Belzutifan in Patients with Advanced Clear Cell Renal Cell Cancer

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