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 from where it first started (primary site) 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.
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). OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive one of the following immunotherapy regimens per physician discretion: nivolumab intravenously (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 orally (PO) twice daily (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 once daily (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. Patients also undergo computed tomography (CT) scan or magnetic resonance imaging (MRI) throughout the trial. Patients may also undergo a bone scan as clinically indicated and blood sample collection throughout the trial. ARM II: Patients undergo SABR on 3 different days over 1-3 weeks and receive immunotherapy as in Arm I. Patients also undergo CT scan or MRI throughout the trial. Patients may also undergo a bone scan as clinically indicated and blood sample collection throughout the trial. After completion of study treatment, patients are followed up every 6 months for 5 years, and then annually for 3 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
240
Given IV
Given PO
Undergo collection of blood
Undergo bone scan
Given PO
Undergo CT
Given IV
Given PO
Undergo MRI
Given IV
Given IV
42 Gy in 3 fractions
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
ACTIVE_NOT_RECRUITINGKingman Regional Medical Center
Kingman, Arizona, United States
RECRUITINGMayo Clinic Hospital in Arizona
Phoenix, Arizona, United States
RECRUITINGUniversity of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
Nephrectomy and radiographic progression-free survival (nrPFS)
Nephrectomy and radiographic progression-free survival time is defined as time from randomization to the date of first radiographic progression, nephrectomy, death, or last negative evaluation (censored). nrPFS rates are estimated using the Kaplan-Meier method. Progression is determined by the Response Evaluation Criteria in Solid Tumors version 1.1 criteria modified for immunotherapy trials (iRECIST).
Time frame: From randomization to last follow-up, up to 8 years
Percentage of participants with complete or partial response
Best overall response is determined by the iRECIST version 1.1.
Time frame: From randomization to disease progression
Percentage of participants with complete or partial response in the primary renal mass
Best overall response is determined by the iRECIST version 1.1.
Time frame: From randomization to disease progression
Radiographic progression-free survival (rPFS)
Radiographic progression-free survival time is defined as time from randomization to the date of first radiographic progression, death, or last negative evaluation (censored). rPFS rates are estimated using the Kaplan-Meier method. Radiographic progression is determined by the iRECIST version 1.1.
Time frame: From randomization to last follow-up, up to 8 years
Nephrectomy and radiographic progression-free survival excluding nephrectomies that were performed for non-protocol specified reasons (nrPFS2)
Nephrectomy and radiographic progression-free survival time (excluding nephrectomies that were performed for non-protocol specified reasons) is defined as time from randomization to the date of first radiographic progression, nephrectomy performed for protocol-stated reasons, death, or last negative evaluation (censored). nrPFS2 rates are estimated using the Kaplan-Meier method. Progression is determined by the iRECIST version 1.1.
Time frame: From randomization to last follow-up, up to 8 years
Overall survival
Overall survival time is defined as time from randomization to the date of death or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method.
Time frame: From randomization to last follow-up, up to 8 years
Second-line therapy-free survival
Second-line therapy-free survival time is defined as time from randomization to the date of the initiation of second-line therapy, death, or last known follow-up (censored). Second-line therapy-free survival rates are estimated using the Kaplan-Meier method.
Time frame: From randomization to last follow-up, up to 8 years
Percentage of participants who undergo cytoreductive nephrectomy
Time frame: From randomization to last follow-up, up to 8 years
Treatment-free survival
Treatment-free survival time is defined as time from the discontinuation of protocol therapy to the date of death or last follow-up (censored). Treatment-free survival rates are estimated using the Kaplan-Meier method.
Time frame: From randomization to last follow-up, up to 8 years
Percentage of participants with grade 3+ and with grade 4+ treatment-related adverse events
Common Terminology Criteria for Adverse Events 5.0 grades adverse event severity from 1=mild to 5=death. Adverse events recorded as possibly, probably, or definitely related to protocol treatment will be considered to be treatment-related.
Time frame: From randomization to last follow-up, up to 8 years
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
PCR Oncology
Arroyo Grande, California, United States
RECRUITINGTower Cancer Research Foundation
Beverly Hills, California, United States
RECRUITINGMills-Peninsula Medical Center
Burlingame, California, United States
RECRUITINGCity of Hope Comprehensive Cancer Center
Duarte, California, United States
ACTIVE_NOT_RECRUITINGUC San Diego Health System - Encinitas
Encinitas, California, United States
RECRUITINGUCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, United States
RECRUITING...and 318 more locations