Phase III Trial of Immunotherapy-Based Combination Therapy With or Without Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma (PROBE Trial)
Overview
- Phase
- Phase 3
- Intervention
- Cytoreductive Nephrectomy
- Conditions
- Metastatic Clear Cell Renal Cell Carcinoma
- Sponsor
- SWOG Cancer Research Network
- Enrollment
- 364
- Locations
- 386
- Primary Endpoint
- Overall survival
- Status
- Recruiting
- Last Updated
- 7 months ago
Overview
Brief Summary
This phase III trial compares the effect of adding surgery to a standard of care immunotherapy-based drug combination versus a standard of care immunotherapy-based drug combination alone in treating patients with kidney cancer that has spread to other places in the body (metastatic). 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. Surgery to remove the kidney, called a nephrectomy, is also considered standard of care; however, doctors who treat kidney cancer do not agree on its benefits. It is not yet known if the addition of surgery to an immunotherapy-based drug combination works better than an immunotherapy-based drug combination alone in treating patients with kidney cancer.
Detailed Description
PRIMARY OBJECTIVE: 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 treatment. BANKING OBJECTIVE: I. To bank specimens for future correlative studies. OUTLINE: PRE-RANDOMIZATION TREATMENT: Treatment naive patients are assigned to 1 of 3 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 pembrolizumab IV on day 1 and axitinib orally (PO) twice daily (BID) on days 1-21. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. REGIMEN III: 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 treatment specified above off-trial. RANDOMIZATION TREATMENT: Between 10-14 weeks from the start of on-trial or off-trial pre-randomization treatment, patients are randomized to 1 of 2 arms. ARM I: Patients receive nivolumab IV, pembrolizumab IV, or avelumab IV on day 1. Patients also receive axitinib PO BID. Cycles with nivolumab repeat every 2 or 4 weeks, cycles with pembrolizumab repeat every 3 weeks, and cycles with avelumab repeat every 2 weeks 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 nivolumab, pembrolizumab, avelumab, and axitinib as in Arm I in the absence of disease progression or unacceptable toxicity. Axitinib should be stopped at least 24 hours prior to surgery. 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.
Investigators
Eligibility Criteria
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:
- •Computed tomography (CT) scan of the chest (can be performed without contrast if CT contrast cannot be given)
- •CT of abdomen and pelvis with contrast OR magnetic resonance imaging (MRI) of the abdomen and pelvis with or without contrast
- •Scans must be performed within the following timeframes:
- •Treatment naive participants must have scans documenting metastatic disease completed within 90 days prior to study registration
- •Previously treated participants must have scans documenting metastatic disease completed within 90 days prior to first dose of systemic 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
Exclusion Criteria
- •STEP 1 REGISTRATION: Participants must not have known active brain metastases. Participants with previously treated brain metastases are eligible if participant has no neurologic signs or symptoms suggestive of brain metastasis. Brain imaging studies are not required. If brain imaging studies are performed, they must be negative for disease
- •STEP 1 REGISTRATION: Participants must not have received the following prior treatment of metastatic renal cell carcinoma:
- •Treatment naive participants must not have received any prior lines of systemic therapy for metastatic renal cell carcinoma beyond the line intended as part of protocol therapy
- •Previously treated participants must not have received any systemic therapy 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:
- •Treatment naive participants must not have received any pre-randomization treatment.
- •Previously treated 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:
- •4 infusions of nivolumab
- •4 infusions of ipilimumab
- •4 infusions of pembrolizumab
Arms & Interventions
Arm 1: Continued Systemic Therapy Only
Nivolumab 240 mg IV 1 q 2 weeks OR Nivolumab 480 mg IV 1 q 4 weeks OR Pembrolizumab 200 mg IV 1 q 3 weeks Axitinib 5 mg oral Daily BID OR Avelumab 10 mg/kg IV 1 q 2 weeks Axitinib 5 mg oral Daily BID
Intervention: Cytoreductive Nephrectomy
Arm 1: Continued Systemic Therapy Only
Nivolumab 240 mg IV 1 q 2 weeks OR Nivolumab 480 mg IV 1 q 4 weeks OR Pembrolizumab 200 mg IV 1 q 3 weeks Axitinib 5 mg oral Daily BID OR Avelumab 10 mg/kg IV 1 q 2 weeks Axitinib 5 mg oral Daily BID
Intervention: Active Comparator
Arm 2: Nephrectomy and Continued Systemic Therapy
Continued systemic therapy as above, plus: Radical or partial nephrectomy may be performed using laparoscopic, open, or robotic approaches. Surgery should be performed within 8 weeks of randomization.
Intervention: Cytoreductive Nephrectomy
Outcomes
Primary Outcomes
Overall survival
Time Frame: From date of randomization to date of death due to any cause, assessed up to 7 years.
Analysis will be intent-to-treat. Evidence suggesting early termination of the trial and a conclusion that the cytoreductive nephrectomy (CN) approach is superior to treatment alone would be if the null hypothesis is rejected at the one-sided 0.005 level. For the second and third interim analyses, the null and alternative hypotheses with respect to survival will be tested, with superiority tested at the one-sided 0.005 level, and futility determined to be met if the (CN versus no CN) hazard ratio is greater than or equal to 1. A proportional hazards model will be fit to estimate the hazard ratio adjusting for the stratification factors as covariates in the model. Will evaluate whether each of the stratification factors are predictive factors of cytoreductive nephrectomy by placing an interaction term corresponding to each stratification factor and treatment arm in the proportional hazards survival model.
Secondary Outcomes
- Overall survival in subset who received assigned protocol treatment(From date of randomization to date of death due to any cause, assessed up to 7 years)
- Change in maximum diameter of primary tumor(From the disease assessment just prior to the start of immunotherapy to the week 12 disease assessment)
- Progression-free survival(From date of randomization to date of first documentation of progression, or death due to any cause, assessed up to 7 years)
- Objective response(Up to 7 years)