Nivolumab Plus Stereotactic Body Radiotherapy in II and III Line of Patients With Metastatic Renal Cell Carcinoma

Study Overview
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Brief Summary
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NIVES study is an ongoing phase II, single arm, multicenter study. In this trial pts received SBRT to one non-brain measurable lesion and concomitant NIVOLUMAB, an anti-programmed cell death (PD-1). Combining SBRT with NIVO may enhance the antitumor immune responses and improve clinical outcomes, how it was demonstrated for other solid tumors with a phenomenon known as the abscopal effect . It was planned to enrolled a total of 68 pts within 12 months. The objective of the current analysis is to describe the first report of safety profile of NIVO in combination with SBRT.

Official Title
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Nivolumab Plus Stereotactic Body Radiotherapy (SBRT) in II and III Line of Patients With Metastatic Renal Cell Carcinoma (mRCC)

Conditions
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Renal Cancer Metastatic

Intervention / Treatment
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* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years on day of signing informed consent Performance status of 0, 1 on the ECOG Performance Scale Histologically confirmed metastatic RCC not suitable for curative-intent local therapy Disease progressed after ≤ 2 prior anti-angiogenic therapies Life expectancy > 12 weeks 2 or more measurable non-brain sites of disease based on RECIST 1.1, whose at least one potentially suitable for treatment with SBRT. In the case of a non measurable bone lesion suitable for treatment with SBRT, even only one measurable non-brain site of disease is allowed Patients are eligible if CNS metastases are treated and patients have neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 14 days prior to enrollment. In addition, patients must either be off corticosteroids or on a stable dose or decreasing dose of ≤ 10 mg daily prednisone (or equivalent) Adequate organ function Exclusion Criteria: Prior therapy with an agent directed at PD-1, PD-L1, or PD-L2 Currently participating in or has participated in a study of an investigational agent or using an investigational device within 2 weeks of the first dose of treatment Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (> 10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease Active brain (CNS) metastases and/or carcinomatous meningitis Prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 14 days prior to the first dose of trial treatment Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection Additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy Evidence of interstitial lung disease, active non-infectious pneumonitis, or a history of grade 3 or greater pneumonitis Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness Live vaccine within 30 days prior to the first dose of trial treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab<br>Hypofractionated radiation will be administered to a metastatic disease site at a dose and schedule of 30 Gy in 3 consecutive fractions. The day of first administration of Nivolumab will be designated as Time 1. Nivolumab will be given as flat dose of 240 mg in intravenous infusion beginning on day 1 every 14 days for 6 months, than switch to 480 mg q4-weekly in responding (CR, PR, SD) patients until PD or unacceptable toxicity . SRT will be administered between the first and second administration of Nivolumab (7 days after the first infusion of Nivolumab). | Drug: Nivolumab<br>* Hypofractionated radiation will be administered to a metastatic disease site at a dose and schedule of 30 Gy in 3 consecutive fractions. The day of first administration of Nivolumab will be designated as Time 1. Nivolumab will be given as flat dose of 240 mg in intravenous infusion beginning on day 1 every 14 days for 6 months, than switch to 480 mg q4-weekly in responding (CR, PR, SD) patients until PD or unacceptable toxicity . SRT will be administered between the first and second administration of Nivolumab (7 days after the first infusion of Nivolumab).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR Objective Response Rate | Objective Response Rate (ORR) , as determined by investigator assessment per RECIST 1.1 Secondary as determined by investigator assessment per RECIST 1.1 | 36 months from the first administration of nivolumab | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS Progression Free Survival | the time between the date of registration and the first date of documented progression, based on invesigator assessment (as per RECIST 1.1 criteria), or death due to any cause, whichever occurs first | 36 months from the first administration of nivolumab | 
| OS Overall Survival | the time from registration to the date of death from any cause | 36 months from the first administration of nivolumab | 
| ORR (Objective Response Rate) of irradiated and non-irradiated metastases and duration of response | determined by investigator assessment per RECIST 1.1 | 36 months from the first administration of nivolumab | 
| Incidence, nature and severity of Adverse Event (safety and tolerability) | All Adverse Events (AEs) and laboratory abnormalities will be collected and graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03 | 36 months from the first administration of nivolumab |