Testing the Addition of Stereotactic Radiation Therapy With Immune Therapy for the Treatment of Patients With Unresectable or Metastatic Renal Cell Cancer, SAMURAI Study

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of renal cellcarcinoma prior to registration

• Node-positive unresectable (TxN1Mx) or metastatic (TxNxM1) based on the followingdiagnostic workup:

• History/physical examination within 45 days prior to registration

• CT/magnetic resonance imaging (MRI) of the chest/abdomen/pelvis within 45 daysprior to registration

• Patients must have IMDC intermediate (1-2 factors) or poor risk disease (>= 3factors)

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Patients with measurable disease (node positive or metastatic) as defined by RECISTversion 1.1 excluding the primary renal tumor

• Patient not recommended for or refused immediate cytoreductive nephrectomy

• Candidate for standard of care therapy with either immuno-oncology (IO)-IO orIO-VEGF combination regimen

• Primary renal tumor measuring 20 cm or less in anterior to posterior dimension onlyon axial imaging

• Age >= 18

• Karnofsky performance status >= 60 within 45 days prior to registration

• Hemoglobin >= 8 g/dL (transfusions are allowed) (within 45 days prior toregistration)

• Platelet count >= 50,000/mm^3 (within 45 days prior to registration)

• Absolute neutrophil count (ANC) >= 1500/mm^3 (within 45 days prior to registration)

• Calculated (Calc.) creatinine clearance >= 30 mL/min (within 45 days prior toregistration)

• For African American patients specifically whose renal function is notconsidered adequate by the formula above, an alternative formula that takesrace into account (Chronic Kidney Disease Epidemiology Collaboration CKD-EPIformula) should be used for calculating the related estimated glomerularfiltration rate (GFR) with a correction factor for African American racecreatinine clearance for trial eligibility, where GFR >= 30 mL/min/1.73m^2 willbe considered adequate

• Total bilirubin =< 1.5 x upper limit of normal (ULN) (except subjects with GilbertSyndrome, who can have total bilirubin < 3.0 mg/dL) (within 45 days prior toregistration)

• Aspartate aminotransferase and alanine aminotransferase (AST and ALT) =< 3 x upperlimit of normal (ULN) or < 5 x ULN if hepatic metastases present (within 45 daysprior to registration)

• Patients with known human immunodeficiency virus (HIV) on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial.Testing is not required for entry into protocol

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

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. Patients with HCV infection who are currently on treatment are eligibleif they have an undetectable HCV viral load

• The patient must agree to use a highly effective contraception, including men withvasectomies if they are having sex with a woman of childbearing potential or with awoman who is pregnant, while on study drug and for 6 months following the last doseof study drug. Childbearing potential is defined as any person who has experiencedmenarche and who has not undergone surgical sterilization (hysterectomy or bilateraloophorectomy) or who is not postmenopausal

• The patient or a legally authorized representative must provide study-specificinformed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

Exclusion Criteria:

• Patients with planned treatment of all metastatic disease with definitive therapyincluding either surgery, ablative (non-palliative) doses of radiation, orintervention of some type (definitive interventional radiology techniques) to ALLmetastatic sites rendering the patient without extra-renal measurable disease.Patients NOT planned for definitive treatment of all metastatic sites are eligible.Lesions radiated palliatively are not eligible for response assessment

• Patients with untreated or unstable brain metastases or cranial epidural disease

• Note: Patients who have been adequately treated with radiotherapy,radiosurgery, or surgery and stable for at least 4 weeks prior to registrationas documented by MRI or CT imaging or deemed stable by clinical investigatorare eligible. Treated brain metastases are defined as having no ongoingrequirement for steroids and no evidence of progression or hemorrhage aftertreatment for at least 4 weeks prior to registration as documented by MRI or CTimaging or deemed stable by clinical investigator

• Prior radiotherapy to the kidney that would result in overlap of radiation therapyfields treatment of the primary tumor

• Any systemic therapy for metastatic renal cell carcinoma (RCC) that was initiated > 90 days before registration, note that prior chemotherapy for a different cancer isallowed (completed > 3 years prior to registration)

• Severe, active comorbidity defined as follows:

• Active autoimmune disease requiring ongoing therapy including systemictreatment with corticosteroids (> 10 mg daily prednisone equivalents) or otherimmunosuppressive medications daily. Inhaled steroids and adrenal replacementsteroid doses > 10 mg daily prednisone equivalents are permitted in the absenceof active autoimmune disease

• History of severe allergic, anaphylactic or other hypersensitivity reactions tochimeric or humanized antibodies

• Active tuberculosis (purified protein derivative [PPD] response without activetuberculosis [TB] is allowed)

• Uncontrolled hypertension (systolic blood pressure [BP] > 190 mmHg or diastolicBP > 110 mmHg)

• Major surgery requiring hospital admission ≤ 28 days prior to registration.

• Any serious (requiring hospital stay or long-term rehab) non-healing wound,ulcer, or bone fracture within 45 days prior to registration

• Any arterial thrombotic (ST elevation myocardial infarction [STEMI], non-STelevation myocardial infarction [NSTEMI], cerebrovascular accident [CVA], etc)events within 180 days prior to registration

• Active New York (NY) Heart Association class 3-4 heart failure symptoms

• Moderate or severe hepatic impairment (Child-Pugh B or C)

• Any history of untreated pulmonary embolism or deep venous thrombosis (DVT)within 180 days prior to registration. (Any asymptomatic or treated pulmonaryembolism or asymptomatic treated deep venous thrombosis > 30 days prior toregistration is allowed)

• Unstable cardiac arrhythmia within 180 days prior to registration

• History of abdominal fistula, gastrointestinal perforation, intra-abdominalabscess, bowel obstruction, or gastric outlet obstruction within 180 days priorto registration

• History of or active inflammatory bowel disease

• Malabsorption syndrome within 45 days prior to registration

• Pregnancy and individuals unwilling to discontinue nursing. For women of childbearing potential must have a negative pregnancy test =< 45 days prior toregistration