A Study of Nivolumab in Combination with 177Lu-girentuximab for Kidney Cancer, STARTLITE 2 Study

Inclusion Criteria

• Locally advanced unresectable or metastatic renal cell carcinoma (RCC) with a component of clear cell histology * Archival tumor tissue will be requested from patients who have undergone biopsy or tumor resection as part of routine clinical care prior to study participation to confirm diagnosis. Patients may undergo pre-treatment biopsy during the screening period if archival tissue is insufficient for baseline analysis. Tumor specimen may include nephrectomy or metastatic site specimen.
• At least one evaluable metastatic lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 on zirconium-89 (89Zr)-girentuximab positron emission tomography (PET)/computed tomography (CT).
• At least one prior line of systemic therapy, including at least one prior treatment with anti PD-1 or PD-L1 antibody.
• Age >= 18 years.
• Karnofsky performance status (KPS) >= 70.
• Absolute neutrophil count (ANC) >= 1500 cells/uL.
• White blood cell (WBC) >= 2500/uL.
• Platelet count >= 100,000/uL (without transfusion within 2 weeks prior to cycle 1, day 1; thrombopoietic agent use is allowed).
• Hemoglobin >= 9.0 g/dL (patients may be transfused or receive erythropoietic treatment to meet this criterion)
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase =< 2.5 x upper limit of normal (ULN), with the following exceptions: * Patients with documented liver metastases: AST and/or ALT =< 5 x ULN * Patients with documented liver or bone metastases: alkaline phosphatase =< 5 x ULN.
• Serum bilirubin =< 2 x ULN * Patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled.
• International Normalized Ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN * This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose.
• Creatinine clearance >= 40mL/min, as measured by the Cockcroft-Gault formula.
• Women of childbearing potential and men are advised to practice double-barrier contraception until a minimum of 6 months after intravenous (IV) 89Zr-girentuximab or177Lu- girentuximab administration. Women of childbearing potential are advised to practice double-barrier contraception until a minimum of 5 months after nivolumab.
• Signed consent form by the participant or a legally authorized representative (LAR).

Exclusion Criteria

• Renal cell carcinoma with no histological evidence of any component of clear cell features. Note: Unclassified RCC with clear cell features is eligible for inclusion.
• Prior treatment with 177Lu- girentuximab.
• Known hypersensitivity to girentuximab or desferrioxamine (DFO).
• Exposure to murine or chimeric antibodies within the last 5 years.
• Previous administration of any radionuclide within 10 half-lives of the same.
• Radiotherapy for RCC within 14 days prior to cycle 1, day 1 except for single-fraction radiotherapy given for the indication of pain control which should be given at least 48 hours prior to cycle 1 day 1 (C1D1).
• Active untreated metastases to the brain > 1 cm or symptomatic (of any size).
• Active untreated metastases to the spinal cord or leptomeningeal disease.
• Patients with uncontrolled pain who are not on a stable pain regimen.
• History of steroid requirement > 10 mg daily prednisone in the past 2 years for autoimmune comorbidities.
• Prior checkpoint inhibitor therapy discontinued due to immune related adverse events.
• Anti-cancer therapy within 2 weeks prior to enrollment.
• Uncontrolled hypercalcemia (>= 1.5 mmol/L ionized calcium or Ca >= 12 mg/dL or corrected serum calcium >= ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab.
• Malignancies other than RCC within 3 years prior to Cycle 1, Day 1, except for those with a negligible risk of metastasis or death, treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent, non-muscle-invasive urothelial carcinoma).
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
• Human immunodeficiency virus (HIV) infection if not well-controlled with antiretroviral therapy.
• Patients with active or chronic hepatitis B or hepatitis C infection.
• Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 3 months, unstable arrhythmias, unstable angina, or ejection fraction (EF) < 50%.
• Patients with known coronary artery disease, congestive heart failure not meeting the above criteria must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.
• History of stroke or transient ischemic attack within 6 months prior to cycle 1, day 1.
• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to cycle 1, day 1.
• Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
• Clinical signs or symptoms of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding.
• Evidence of abdominal free air not explained by paracentesis or recent surgical procedure.
• Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture.
• Major surgery within 4 weeks prior to enrollment (biopsy or line placement can be performed up to 24 hours prior to enrollment).
• Pregnant and lactating women.
• Patients in whom nivolumab treatment is not feasible for any reason (including financial/insurance).