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

Introduction

• Org Study ID: S1931
• NTC ID: NCT04510597
• Lead Sponsor Name: National Cancer Institute (NCI)

Overall Status

Conditions

• Chromophobe Renal Cell Carcinoma
• Clear Cell Renal Cell Carcinoma
• Papillary Renal Cell Carcinoma
• Renal Medullary Carcinoma
• Translocation/TFE Renal Cell Carcinoma
• Unclassified Renal Cell Carcinoma

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.

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
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
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 REGISTRATION: Participants must have at least one of the following scans performed 12 weeks (+/- 2 weeks) after starting pre-randomization 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 treatment. Participants with complete response in all metastatic sites are not eligible to randomize to Step 2

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

Stable disease
Partial response

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

STEP 2 REGISTRATION: Participants must plan to continue the immune-based therapy 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 the minimum 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 42 days of randomization
STEP 2 REGISTRATION: Participants must be a surgical candidate as determined by study urologist. The urology consult should be done within 42 days prior to randomization
STEP 2 REGISTRATION: Participants must have a complete physical examination and medical history within 28 days prior to randomization
STEP 2 REGISTRATION: Participants must have a Zubrod performance status of 0-1 within 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 to randomization)
STEP 2 REGISTRATION: 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)

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
7 infusions of avelumab

STEP 1 REGISTRATION: Participants must not have received immunotherapy for any cancer within the following timeframes:

Treatment naive participants must not have received any immunotherapy within a year of registration
Previously treated participants must not have received any other immunotherapy within a year of the start of off protocol specified pre-randomization treatment
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 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 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 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 in complete remission, or any other cancer from which the participant has been disease free for two years