Phase 1b/2 Study of Combination 177Lu Girentuximab Plus Cabozantinib and Nivolumab in Treatment naïve Patients With Advanced Clear Cell RCC

To learn if giving 177Lu girentuximab in combination with cabozantinib plus nivolumab can help to control advanced clear cell renal cell carcinoma (ccRCC).

Inclusion Criteria:Has the ability to understand and willingness to sign a written ICF before the performance of any study-specific procedures on this protocol and 2022-0515Age ≥ 18 yearsHas locally advanced or metastatic RCC with predominantly clear cell subtypeHas at least one measurable lesion as defined by RECIST version 1.1Has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1Has adequate organ function defined as follows:a. Absolute neutrophil count ≥ 1,500/µL, Hgb level ≥ 9 g/dL and platelet count (Plt) i. ≥ 100,000/µL without transfusion or growth factor support within 2 weeks prior to obtaining the hematology values at screening; b. Creatinine clearance ≥ 40 mL/min/1.73m2 c. Transaminase levels (AST/ALT) ≤ 3.0 × upper limit of normal (ULN); total bilirubin i. (TBILI) ≤ 1.5 mg/dL in the absence of Gilbert's diseaseWomen of child beariring potential must have a negative serum preganancy test within 7 days before first study drug administrationFemale patients of child bearing potential, or a male patients with a female partner of child-bearing potential (defined as all women physiologically capable of becoming pregnant), must agree to use a highly effective method of contraception during screening, during the period of drug administration and for 120 days after stopping study drug administration. Highly effective contraception methods include the following:Total abstinence (defined as refraining from heterosexual intercourse during the entire period outlined above),Male or female sterilization, orUse of at least one of the following:Use of oral, injectable, transdermal, intravaginal, or implantable hormonal methods of contraception i. Combined estrogen and progestogen containing hormonal contraception associated with inhibition of ovulation ii. Progestogen-only hormonal contraception associated with inhibition of ovulation c. Placement of an intrauterine device or intrauterine systemAble to swallow oral medicationsAble to provide tumor tissue sample (archival or recent acquisition)Patients with brain metastases are eligible providing other measurable disease exists and brain lesions are controlled for one month (requiring no therapy) and are not life threatening.Exclusion Criteria:Has received treatment with any frontline systemic therapy for metastatic RCCHas a history of leptomeningeal disease or spinal cord compressionHas a history of autoimmune disease requiring active therapyHas a history of brain metastases except:Patients may be enrolled if they have treated brain metastases with no evidence of progression or hemorrhage after therapy for brain metastases (e.g. radiation therapy, surgery, radiosurgery) ANDPatients may be enrolled if they do not require ongoing treatment with dexamethasone or anti-epileptic drugsHas had radiation therapy for bone metastases within 2 weeks, or any other external radiation therapy (5 days or longer) to sites other than bone, within 4 weeks before administration of the first dose of study treatment. Patients with clinically relevant ongoing major complications from prior radiation therapy are not eligible.Has uncontrolled or poorly controlled hypertension, as defined by a sustained blood pressure (BP) > 140/90 with or without antihypertensive treatmentHas had any major cardiovascular event within 6 months prior to study drug administration including but not limited to myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack, pulmonary embolism, clinically significant ventricular arrhythmias (e.g. sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes) or New York Heart Association Class III or IV heart failureHas any other clinically significant cardiac, respiratory, or other medical or psychiatric condition that might interfere with participation in the trial or interfere with the interpretation of trial results, in the opinion of the investigator or medical monitorHas an active infection requiring systemic treatmentIs participating in another therapeutic clinical trialIs receiving chronic concomitant treatment with strong CYP3A4 inducers or CYP3A4 inhibitorsHas manifestations of malabsorption due to prior gastrointestinal (GI) surgery or GI diseaseHas GI disorders including those associated with a high risk of perforation or fistula formation:Tumors invading the GI-tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstructionAbdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before administration of the first dose of study treatment. Note: complete healing of an intra-abdominal abscess must be confirmed before administration of the first dose of study treatmentHas tumor invading or encasing any major blood vesselsHas other clinically significant disorders such as:Serious non-healing wound/ulcer/bone fractureModerate to severe hepatic impairment (Child-Pugh B or C).Requirement for hemodialysis or peritoneal dialysisHistory of solid organ transplantationHas had major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 2 months before the first study drug administration. Complete wound healing from major surgery must have occurred 1 month before the first study drug administration and from minor surgery (e.g., simple excision, tooth extraction) at least 10 days before the first study drug administration. Patients with clinically relevant ongoing complications from prior surgery are not eligibleHas a prior or concomitant invasive malignancy other than RCC with the exception of adequately treated basal or squamous cell carcinoma of the skin, cervical carcinoma in situ or any other malignancy from which the patient has remained disease free for more than 2 years.