Comparing the Outcome of Immunotherapy-Based Drug Combination Therapy With or Without Surgery to Remove the Kidney in Metastatic Kidney Cancer, the PROBE Trial

Inclusion Criteria:

• STEP 1 REGISTRATION: Participants must have a histologically proven diagnosis ofclear cell or non-clear cell renal cell carcinoma. Participants with collecting ductcarcinoma histology are not eligible. Participants with multifocal or bilateraltumors are eligible

• STEP 1 REGISTRATION: Participants must have primary tumor in place

• STEP 1 REGISTRATION: Participants must have the following scans performed, showingclinical evidence of measurable or non-measurable metastatic disease:

• Computed tomography (CT) scan of the chest (can be performed without contrastif CT contrast cannot be given)

• CT of abdomen and pelvis with contrast OR magnetic resonance imaging (MRI) ofthe abdomen and pelvis with or without contrast

Scans must be performed within the following timeframes:

• Treatment naive participants must have scans documenting metastatic diseasecompleted within 90 days prior to study registration

• Previously treated participants must have scans documenting metastatic diseasecompleted within 90 days prior to first dose of systemic treatment

• STEP 1 REGISTRATION: Participants with symptomatic metastases may have receivedpalliative radiotherapy or receive palliative radiotherapy after registration

• STEP 1 REGISTRATION: Participants must have no clear contraindications tonephrectomy

• STEP 1 REGISTRATION: Participants must be offered the opportunity toparticipate in specimen bank. With participant consent, specimens must becollected and submitted via the Southwest Oncology Group (SWOG) SpecimenTracking System

• STEP 1 REGISTRATION: Participants must be informed of the investigationalnature of this study and must sign and give informed consent in accordance withinstitutional and federal guidelines

• STEP 1 REGISTRATION: As part of the Oncology Patient Enrollment Network (OPEN)registration process the treating institution's identity is provided in orderto ensure that the current (within 365 days) date of institutional review boardapproval for this study has been entered in the system

• STEP 2 REGISTRATION: Participants must have at least one of the following scansperformed 12 weeks (+/- 2 weeks) after starting pre-randomization treatment

• CT scan of the chest (can be performed without contrast if CT contrast cannot begiven)

• CT of abdomen and pelvis with contrast OR MRI of the abdomen and pelvis with orwithout contrast Scans must be performed within 28 days prior to randomization.Response should be assessed by comparing with a CT or MRI of the chest, abdomen andpelvis obtained prior to starting pre-randomization treatment. Participants withcomplete response in all metastatic sites are not eligible to randomize to Step 2

• STEP 2 REGISTRATION: Participants must have one of the following objectivestatuses after 12 weeks of pre-randomization treatment

• Stable disease

• Partial response

• The treating investigator believes the patient is deriving clinical benefit fromsystemic therapy AND have Zubrod performance status 0-1

• STEP 2 REGISTRATION: Participants must plan to continue the immune-basedtherapy received during pre-randomization treatment

• STEP 2 REGISTRATION: Participants must be randomized on or between the 11th and 14th week of protocol-directed pre-randomization treatment therapy

• STEP 2 REGISTRATION: Participants must have received at least one of theminimum amounts of immunotherapy:

• 2 infusions of nivolumab + 1 infusion of ipilimumab

• 2 infusions of pembrolizumab

• 2 infusions of avelumab

• STEP 2 REGISTRATION: Participants must have a planned surgery date within 42days of randomization

• STEP 2 REGISTRATION: Participants must be a surgical candidate as determined bystudy urologist. The urology consult should be done within 42 days prior torandomization

• STEP 2 REGISTRATION: Participants must have a complete physical examination andmedical history within 28 days prior to randomization

• STEP 2 REGISTRATION: Participants must have a Zubrod performance status of 0-1within 28 days prior to randomization

• STEP 2 REGISTRATION: Total bilirubin =< institutional upper limit of normal (ULN) (within 28 days prior to randomization)

• STEP 2 REGISTRATION: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x institutional upper limit of normal (ULN) (within 28 days prior torandomization)

• STEP 2 REGISTRATION: Serum creatinine =< 1.5 x the institutional upper limit ofnormal (IULN) OR measured OR calculated creatinine clearance >= 50 mL/min usingthe Cockcroft-Gault Formula) (must have been drawn and processed within 28 daysprior to randomization)

Exclusion Criteria:

• STEP 1 REGISTRATION: Participants must not have known active brain metastases.Participants with previously treated brain metastases are eligible if participanthas no neurologic signs or symptoms suggestive of brain metastasis. Brain imagingstudies are not required. If brain imaging studies are performed, they must benegative for disease

• STEP 1 REGISTRATION: Participants must not have received the following priortreatment of metastatic renal cell carcinoma:

• Treatment naive participants must not have received any prior lines of systemictherapy for metastatic renal cell carcinoma beyond the line intended as part ofprotocol therapy

• Previously treated participants must not have received any systemic therapy formetastatic renal cell carcinoma beyond the one regimen received off protocol asspecified in Step 1 pre-randomization treatment

• STEP 1 REGISTRATION: Participants must not have received more than the followingamounts protocol-directed pre-randomization treatment:

• Treatment naive participants must not have received any pre-randomizationtreatment.

• Previously treated participants must not be planning to receive any additionaltreatment prior to Step 2 randomization, and must not have received more thanthe following amounts of pre-randomization treatment:

• 4 infusions of nivolumab

• 4 infusions of ipilimumab

• 4 infusions of pembrolizumab

• 7 infusions of avelumab

• STEP 1 REGISTRATION: Participants must not have received immunotherapy for anycancer within the following timeframes:

• Treatment naive participants must not have received any immunotherapy within ayear of registration

• Previously treated participants must not have received any other immunotherapywithin a year of the start of off protocol specified pre-randomizationtreatment

• STEP 1 REGISTRATION: Participants must not have a solitary kidney and not have atransplanted kidney

• STEP 1 REGISTRATION: No other prior malignancy is allowed except for the following:adequately treated basal cell or squamous cell skin cancer, any in situ or T1cancer, adequately treated stage I or II cancer from which the participant iscurrently in complete remission, or any other cancer from which the participant hasbeen disease free for at least two years

• STEP 1 REGISTRATION: Participants must not have been previously diagnosed with amedical condition that makes them ineligible for immune based combination therapy ornephrectomy

• STEP 2 REGISTRATION: Participants must not show progression in the primary tumor.Participants who are considered to have pseudo progression are allowed

• STEP 2 REGISTRATION: Participants must not have known active brain metastases.Participants with previously treated brain metastases are eligible if participanthas no neurologic signs or symptoms suggestive of brain metastasis. Brain imagingstudies are not required. If brain imaging studies are performed, they must benegative for disease

• STEP 2 REGISTRATION: No other prior malignancy is allowed except for the following:adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer,adequately treated stage I or II cancer from which the participant is currently incomplete remission, or any other cancer from which the participant has been diseasefree for two years