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Comparing the Outcome of Immunotherapy-Based Drug Combination Therapy with or without Surgery to Remove the Kidney in Metastatic Kidney Cancer, the PROBE Trial
Trial Status: active
This phase III trial compares standard systemic treatment alone versus standard systemic treatment plus surgery to remove all or part of the affected kidney (cytoreductive nephrectomy) in treating patients with kidney cancer that has spread to other places in the body (metastatic). Standard systemic therapy for this type of cancer is immunotherapy-based combination therapy which may shrink the tumor and stimulate the immune system to attack the cancer. Systemic therapy is a type of treatment when drugs travel through the blood to cells all over the body. Immunotherapy with monoclonal antibodies, such as nivolumab, ipilimumab, pembrolizumab, and avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Axitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cytoreductive nephrectomy is a surgical procedure to remove as many cancer cells from the kidney as possible. This study will help determine whether addition of surgery to standard of care systemic therapy is better than systemic therapy alone for the treatment of metastatic kidney cancer.
Inclusion Criteria
STEP 1 REGISTRATION: Participants must have a histologically proven diagnosis of clear cell or non-clear cell renal cell carcinoma. Participants with collecting duct carcinoma histology are not eligible. Participants with multifocal or bilateral tumors are eligible
STEP 1 REGISTRATION: Participants must have primary tumor in place
STEP 1 REGISTRATION: Participants must have the following scans performed, showing clinical evidence of measurable or non-measurable metastatic disease:
* CT scan of the chest (can be performed without contrast if CT contrast cannot be given)
* CT of abdomen and pelvis with contrast OR MRI of the abdomen and pelvis with or without contrast
Scans must be performed within the following timeframes:
* Immunotherapy naive participants must have scans documenting metastatic disease completed within 90 days prior to study registration
* Pre-randomization completed participants must have scans documenting metastatic disease completed within 90 days prior to first dose of systemic immunotherapy treatment
STEP 1 REGISTRATION: Participants with treated brain metastases must have no evidence of progression on follow-up brain imaging after central nervous system (CNS)-directed therapy. Brain imaging studies are not required, unless clinically indicated
STEP 1 REGISTRATION: Participants must not have received the following prior treatment of metastatic renal cell carcinoma:
* Immunotherapy naive participants must not have received any prior lines of systemic immunotherapy for metastatic renal cell carcinoma
* Pre-randomized completed participants must not have received any systemic immunotherapy for metastatic renal cell carcinoma beyond the one regimen received off protocol as specified in Step 1 pre-randomization treatment
STEP 1 REGISTRATION: Participants must not have received more than the following amounts protocol-directed pre-randomization treatment:
* Immunotherapy naive participants must not have received any pre-randomization treatment
* Pre-randomization completed participants must not be planning to receive any additional treatment prior to Step 2 randomization, and must not have received more than the following amounts of pre-randomization treatment:
** 5 total: infusions of nivolumab at 3 mg/kg plus 1 dose (240 mg or 480 mg)
** 7 infusions of nivolumab at 240mg dose
** 4 infusions of nivolumab at 480mg dose
** 4 infusions of ipilimumab
** 5 infusions of pembrolizumab at 200mg dose
** 3 infusions of pembrolizumab at 400mg dose
** 7 infusions of avelumab
STEP 1 REGISTRATION: Participants must not have received immunotherapy for any cancer within the following timeframes:
* Immunotherapy naive participants must not have received any immunotherapy within 6 months prior to registration
* Pre-randomization completed participants must not have received any other immunotherapy within 6 months of the start of off protocol specified pre-randomization treatment
STEP 1 REGISTRATION: Participants with symptomatic metastases may have received palliative radiotherapy or receive palliative radiotherapy after registration
STEP 1 REGISTRATION: Participants must have no clear contraindications to nephrectomy
STEP 1 REGISTRATION: Participants must be >= 18 years old
STEP 1 REGISTRATION: Participants must not have a solitary kidney and not have a transplanted 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 T1 cancer, adequately treated stage I or II cancer from which the participant is currently in complete remission, or any other cancer from which the participant has been disease free for at least two years
STEP 1 REGISTRATION: Participants must not have been previously diagnosed with a medical condition that makes them ineligible for immune based combination therapy or nephrectomy
STEP 1 REGISTRATION: Participants must be offered the opportunity to participate in specimen bank. With participant consent, specimens must be collected and submitted via the Southwest Oncology Group (SWOG) Specimen Tracking System
STEP 1 REGISTRATION: Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines. For participants with impaired decision making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and Central Institutional Review Board (CIRB) regulations
STEP 1 REGISTRATION: As part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
STEP 2 RANDOMIZATION: Participants must have at least one of the following scans performed 12 weeks (+/- 2 weeks) after starting pre-randomization immunotherapy treatment
* CT scan of the chest (can be performed without contrast if CT contrast cannot be given)
* CT of abdomen and pelvis with contrast OR MRI of the abdomen and pelvis with or without 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 and pelvis obtained prior to starting pre-randomization immunotherapy treatment. Participants with complete response in all metastatic sites are not eligible to randomize to Step 2
STEP 2 RANDOMIZATION: Participants must have one of the following objective statuses after 12 weeks of pre-randomization immunotherapy treatment
* Stable disease
* Partial response
* The treating investigator believes the participant is deriving clinical benefit from systemic immunotherapy AND have Zubrod performance status 0-1
STEP 2 RANDOMIZATION: Participants must plan to continue the immune-based therapy received during pre-randomization immunotherapy treatment
STEP 2 RANDOMIZATION: Participants must not show progression in the primary tumor. Participants who are considered to have pseudo progression are allowed
STEP 2 RANDOMIZATION: Participants with treated brain metastases must have no evidence of progression on follow-up brain imaging after CNS-directed therapy. Brain imaging studies are not required, unless clinically indicated
STEP 2 RANDOMIZATION: Participants must be registered to Step 2 Randomized on or between week 11, day 1, and week 14, day 7 of protocol-directed pre-randomization immunotherapy treatment
STEP 2 RANDOMIZATION: Participants must have received at least one of the minimum amounts of immunotherapy:
* 2 infusions of nivolumab + 1 infusion of ipilimumab (if given in combination)
* 2 infusions of pembrolizumab at 200mg dose
* 1 infusion of pembrolizumab at 400mg dose
* 2 infusions of avelumab
* 2 infusions of nivolumab (if not given in combination with ipilimumab)
STEP 2 RANDOMIZATION: Participants must have a planned surgery date within 42 days of randomization
STEP 2 RANDOMIZATION: Participants must be a surgical candidate as determined by study urologist. The urology consult must be done within 42 days prior to randomization
STEP 2 RANDOMIZATION: Participants must have a complete physical examination and medical history within 28 days prior to randomization
STEP 2 RANDOMIZATION: Participants must have a Zubrod performance status of 0-1 within 28 days prior to randomization
STEP 2 RANDOMIZATION: Total bilirubin =< 2 x institutional upper limit of normal (ULN) (within 28 days prior to randomization)
STEP 2 RANDOMIZATION: Aspartate aminotransferase (AST) =< 3 x institutional ULN, unless liver metastases. Participants with liver metastases must have AST =< 5 x institutional ULN (within 28 days prior to randomization)
STEP 2 RANDOMIZATION: Alanine aminotransferase (ALT) =< 3 × institutional ULN, unless liver metastases. Participants with liver metastases must have ALT =< 5 × institutional ULN (within 28 days prior to randomization)
STEP 2 RANDOMIZATION: Serum creatinine =< 1.5 x the institutional upper limit of normal (IULN) OR measured OR calculated creatinine clearance >= 50 mL/min using the Cockcroft-Gault Formula (must have been drawn and processed within 28 days prior to randomization)
STEP 2 RANDOMIZATION: 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 in complete remission, or any other cancer from which the participant has been disease free for two years
Additional locations may be listed on ClinicalTrials.gov for NCT04510597.
I. To compare overall survival in participants with newly diagnosed metastatic renal cell carcinoma who are randomized to receive immune checkpoint inhibitor-based combination treatment plus cytoreductive nephrectomy versus immune checkpoint inhibitor-based combination treatment alone.
SECONDARY OBJECTIVES:
I. To compare overall survival between arms in the subset who received their assigned protocol treatment.
II. To assess complications of nephrectomy and post-randomization drug toxicities.
III. To compare objective response rate in metastatic sites between the arms in participants with measurable metastatic disease.
IV. To assess change in diameter of primary tumor at week 12 disease assessment in participants who have received pre-randomization immunotherapy treatment.
BANKING OBJECTIVE:
I. To bank specimens for future correlative studies.
OUTLINE:
PRE-RANDOMIZATION IMMUNOTHERAPY TREATMENT: Immunotherapy naive patients are assigned to 1 of 5 immunotherapy treatment regimens per standard of care.
REGIMEN I: Patients receive nivolumab intravenously (IV) and ipilimumab IV. Treatment repeats every 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV on day 1. Cycles repeat every 2-4 weeks in the absence of disease progression or unacceptable toxicity.
REGIMEN II: Patients receive nivolumab IV on day 1 and cabozantinib orally (PO) daily (QD). Cycles repeat every 2-4 weeks in the absence of disease progression or unacceptable toxicity.
REGIMEN III: Patients receive pembrolizumab IV on day 1 and axitinib PO twice daily (BID) on days 1-21. Cycles repeat every 3-6 weeks in the absence of disease progression or unacceptable toxicity.
REGIMEN IV: Patients receive pembrolizumab IV on day 1 and lenvatinib PO QD. Cycles repeat every 3-6 weeks in the absence of disease progression or unacceptable toxicity.
REGIMEN V: Patients receive avelumab IV on day 1 and axitinib PO BID on days 1-14. Cycles repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.
NOTE: Some patients may have already completed the standard of care pre-randomization immunotherapy treatment specified above off-trial.
RANDOMIZATION IMMUNOTHERAPY TREATMENT: Between 10-14 weeks from the start of on-trial or off-trial pre-randomization immunotherapy treatment, patients are randomized to 1 of 2 arms.
ARM I: Patients receive 1 of 5 pre-randomization immunotherapy treatments as detailed above. Patients continue systemic immunotherapy in the absence of disease progression or unacceptable toxicity.
ARM II: Within 42 days following randomization, patients undergo radical or partial nephrectomy in addition to continuing systemic immunotherapy as in arm I. Patients continue systemic immunotherapy in the absence of disease progression or unacceptable toxicity.
All patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) scans throughout the trial, as well as collection of blood samples during screening and on study.
After completion of trial treatment, patients are followed up every 3 months for the first year, every 6 months for years 2 and 3, and then annually for up to 7 years from randomization.