Title
NRG-GU012, Randomized Phase II Stereotactic Ablative Radiation Therapy (SABR) for Metastatic Unresected Renal Cell Carcinoma (RCC) Receiving Immunotherapy (SAMURAI)

Description
This phase II trial tests whether the addition of radiation to the primary tumor, typically given with stereotactic ablative radiation therapy (SABR), in combination with standard of care immunotherapy improves outcomes in patients with renal cell cancer that is not recommended for surgery and has spread to other places in the body (metastatic). Radiation therapy uses high energy photons to kill tumor cells and shrink tumors. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses of radiation over a shorter period and cause less damage to normal tissue. Immunotherapy with monoclonal antibodies, such as nivolumab, ipilimumab, avelumab, and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Axitinib, cabozantinib, and lenvatinib are in a class of medications called antiangiogenic agents. They work by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Giving SABR in combination with standard of care immunotherapy may help shrink or stabilize the cancer in patients with renal cell cancer.

Objective
PRIMARY OBJECTIVE:

I. To determine whether the addition of stereotactic ablative radiotherapy (SABR) to the primary tumor in combination with immunotherapy improves outcomes compared to immunotherapy alone in patients with metastatic, unresected, renal cell carcinoma (RCC). The primary endpoint is nephrectomy and radiographic progression-free survival (nrPFS) with progression determined as per iRECIST criteria.

SECONDARY OBJECTIVES:

I. To assess the safety, toxicity and tolerability of the two treatment strategies as defined by Common Terminology Criteria for Adverse Events (CTCAE) version 5 in each treatment arm.

II. To assess the objective response rate (ORR) by Immune-related Response Evaluation Criteria in Solid Tumors (iRECIST) in each treatment arm.

III. Nephrectomy and radiographic progression-free survival excluding nephrectomies that were performed for non-protocol specified indications (nephrectomy and radiographic progression-free survival [nrPFS]2).

IV. Radiographic progression-free survival (rPFS). V. To assess overall survival (OS) in each treatment arm. VI. To assess the time to subsequent second-line therapy or death in each treatment arm.

VII. To assess the rate of cytoreductive nephrectomy in each treatment arm. VIII. To assess treatment-free survival in patients who discontinue therapy for reason other than radiographic disease progression.

IX. To assess the ORR by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and iRECIST in the primary renal mass.

EXPLORATORY OBJECTIVES:

I. To assess composite nrPFS in the predefined histological subgroups below:

Ia. Clear cell versus non-clear cell histology. Ib. International Metastatic RCC database consortium (IMDC) intermediate versus poor risk group.

Ic. Systemic treatment with immunotherapy-immunotherapy combination versus immunotherapy-vascular endothelial growth factor (VEGF) targeted therapy combination.

Id. Sarcomatoid versus non sarcomatoid variant. II. To identify prognostic and predictive biomarkers of response to SABR in the context of immunotherapy based treatment via assessment of tissue and blood based biomarkers.

III. To evaluate the abscopal effect of SABR with systemic therapy. IIIa. Compare ORR in non-irradiated target lesions in the control arm patients undergoing immunotherapy alone to the experimental arm undergoing SABR + immunotherapy.

IV. To evaluate the impact of treatment on level of inferior vena cava (IVC) thrombus.

V. To compare accruing center identified iRECIST progression and centrally identified iRECIST progression events on computed tomography (CT).

Treatment Active Comparator: Arm I (standard of care immunotherapy)
Patients receive one of the following immunotherapy regimens per physician discretion: nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes every 3 weeks for 4 doses followed by nivolumab IV over 30 minutes every 2 or 4 weeks; pembrolizumab IV over 30 minutes every 3 or 6 weeks and axitinib PO BID; avelumab IV over 60 minutes every 2 weeks and axitinib PO BID; nivolumab IV over 30 minutes every 2 or 4 weeks and cabozantinib PO QD; OR pembrolizumab IV over 30 minutes every 3 or 6 weeks and lenvatinib PO QD. Treatment with immunotherapy continues in the absence of disease progression or unacceptable toxicity.

Experimental: Arm II (SABR, standard of care immunotherapy)
Patients undergo SABR on 3 different days over 1-3 weeks and receive immunotherapy as in Arm I.

Key Eligibility Inclusion Criteria:

Pathologically (histologically or cytologically) proven diagnosis of renal cell carcinoma prior to registration

Node-positive unresectable (TxN1Mx) or metastatic (TxNxM1) based on the following diagnostic workup:



History/physical examination within 45 days prior to registration

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



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

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

Patients with measurable disease (node positive or metastatic) as defined by RECIST version 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 or IO-VEGF combination regimen

Primary renal tumor measuring 8 cm or less in anterior to posterior dimension only on 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 to registration)

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 to registration)



For African American patients specifically whose renal function is not considered adequate by the formula above, an alternative formula that takes race into account (Chronic Kidney Disease Epidemiology Collaboration CKD-EPI formula) should be used for calculating the related estimated glomerular filtration rate (GFR) with a correction factor for African American race creatinine clearance for trial eligibility, where GFR >= 30 mL/min/1.73m^2 will be considered adequate



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

Aspartate aminotransferase and alanine aminotransferase (AST and ALT) =< 3 x upper limit of normal (ULN) or < 5 x ULN if hepatic metastases present (within 45 days prior to registration)

Patients with known human immunodeficiency virus (HIV) on effective anti-retroviral therapy 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 HBV viral load must be undetectable on suppressive therapy, if indicated

Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load

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

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

Applicable Disease Sites
Kidney

Participating Institutions
UW Cancer Center at ProHealth; UW Health 1 S. Park Medical Center; UW Health Eastpark Medical Center; UW Health University Hospital