Nivolumab and Stereotactic Ablative Radiation Therapy (SAbR) for Metastatic Clear Cell Renal Cell Carcinoma

Study Overview
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Brief Summary
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Nivolumab (brand name Opdivo): IV, administered per standard of care according to institutional guidelines at the discretion of the treating medical oncologist, until disease progression or unacceptable toxicity; SABR, dose variable, in 1-3 fractions.

Detailed Description
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A single institution, safety lead-in phase II trial with SAbR to multiple metastatic sites concurrently administered with Nivolumab for patients with metastatic clear cell renal cell cancer who have failed at least one anti-angiogenic therapy.

Official Title
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Phase II Trial of Nivolumab and Stereotactic Ablative Radiation Therapy (SAbR) for Metastatic Clear Cell Renal Cell Carcinoma (mRCC)

Conditions
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Metastatic Clear Cell Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Nivolumab
* Radiation: SAbR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 18 years of age Willing and able to provide consent Pathologic diagnosis of metastatic RCC with clear cell component Measurable disease in at least 2 non-radiated sites. Progression or intolerance to at least one prior systemic anti-angiogenic therapy. Eligible for extra-CNS SAbR to 1-6 sites of disease Must have received at least one prior anti-angiogenic therapy in the advanced or metastatic setting. Prior cytokine therapy (eg, IL-2, IFN-α), vaccine therapy, or treatment with cytotoxic therapy is also allowed but not any other drug specifically targeting T-cell co-stimulation or checkpoint pathways. Previous treatment with surgery, radiation, chemotherapy, targeted agents (see above) are allowed provided that: Chemotherapy/Major surgery was administered > 14 days before the start Nivolumab; Minor surgery, radiation, or any targeted agents were administered > 7 days before the start of Nivolumab Performance status ECOG 0, 1, 2 or 3. Adequate organ and marrow function as defined below (obtained within 14 days of first dose of drug): leukocytes≥ 2,000/mcL absolute neutrophil count ≥ 1,500/mcL platelets ≥ 50,000/mcl total bilirubin ≤ 2mg/dL AST(SGOT)/ALT(SPGT) ≤ 3 X institutional upper limit of normal Women of child-bearing potential female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: must have a negative serum or urine pregnancy test within 24 hours prior to the start of investigational product. Women must not be breastfeeding. must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and contraception should be continued for a period of 30 days plus the time required for the investigational drug to undergo five half lives. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Contraception should be continued for a period of 90 days plus the time required for the investigational drug to undergo five half lives. This is equivalent to 31 weeks after discontinuation of Nivolumab. Adequate Renal function with Cr ≤ 2.5 mg/dL. Exclusion Criteria: Subjects who have had major surgery (such as nephrectomy) or chemotherapy within 2 weeks prior to first dose of drug Subjects who have had radiation therapy within 2 weeks prior to first dose of drug Uncontrolled adrenal insufficiency or active chronic liver disease Any history of CNS metastases that is not adequately treated with surgery or SABR >14 days prior. Prior treatment with any anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways. Any positive history for HIV/AIDS, HTLV, hepatitis B or hepatitis C virus indicating acute or chronic infection. Any active known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to the first dose of study drug. Inhaled steroids and adrenal replacement steroid doses up to 10 mg daily prednisone equivalent are permitted (although not encouraged) in the absence of active autoimmune disease. Subjects with life expectancy < 6 months Subjects receiving any other investigational or standard antineoplastic agents. Prior malignancies active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, breast?, or etc. Psychiatric illness/social situations that would limit consenting and compliance with study requirements. Patients with history of hypersensitivity to monoclonal antibodies Subjects who are pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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 and SABR<br>Nivolumab alone: IV, administered per standard of care according to institutional guidelines at the discretion of the treating medical oncologist, until disease progression or unacceptable toxicity. SABR, dose variable, in 1-3 fractions. | Drug: Nivolumab<br>* Nivolumab IV, administered per standard of care according to institutional guidelines at the discretion of the treating medical oncologist<br>* Other names: Opdivo;Radiation: SAbR<br>* SAbR (1-3 lesions)<br>* Other names: Stereotactic Ablative Radiation Therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (RR) | The primary objective of the randomized phase II trial will be to increase the RR (response rate) of treatment with Nivolumab by the concurrent administration of SAbR. The assessment of RR will be based on the evaluation of ir-RECIST (Response Evaluation Criteria in Solid Tumors) criteria and radiated lesions will be excluded from target lesions. Treatment response will be measured using both the RECIST and immune related RECIST criteria (ir-RECIST), a minor modification of RECIST 1.1 for immunotherapy. Radiated lesions will be excluded from target lesions. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | To evaluate the overall survival (OS), which is defined as the time between date of registration and the date of death due to any cause. In analyzing OS, we will take into account the MSKCC (Memorial Sloan Kettering Cancer Center) prognostic criteria for mRCC (Metastatic Renal Cell Carcinoma) and compare our data to historical controls in the appropriate risk category. | 3 years | 
| Progression Free Survival | To evaluate progression free survival (PFS), which is defined as the time between date of registration and the first date of documented disease progression or date of death due to any cause. Progression will be defined according to the ir-RECIST (Response Evaluation Criteria in Solid Tumors) criteria and verified by a second set of imaging at least 6 weeks apart. | 3 years | 
| Complete Response Rate | To evaluate and compare complete response rate in each arm, which is defined as the percentage of patients who show complete response as per ir-RECIST (Response Evaluation Criteria in Solid Tumours) criteria. Treatment response will be measured using both the RECIST and immune related RECIST criteria (ir-RECIST), a minor modification of RECIST 1.1 for immunotherapy. Radiated lesions will be excluded from target lesions. | 3 years | 
| Time to Progression | To evaluate and compare time to progression (TTP), which is defined as time between date of registration and date of documented progression, between the experimental and control arms. Progression will be defined according to the ir-RECIST (Response Evaluation Criteria in Solid Tumors) criteria and verified by a second set of imaging at least 6 weeks apart. | 3 years | 
| Median Response Duration | To evaluate median response duration, which is defined as the time between the date of PR (partial response) was first seen until date of progression. | 3 years | 
| Median Response Duration to CR (Complete Response) | To evaluate median duration, which is defined as the time between the date of CR (complete response) was first seen until date of progression. | 3 years | 
| Adverse Events | To evaluate the tolerability and toxicity as measured according to CTCAE v4.0. Adverse events will be graded by a numerical score according to the defined NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) and version number 4.0. Adverse events not specifically defined in the NCI CTCAE will be scored on the Adverse Event log according to the general guidelines provided by the NCI CTCAE and as outlined below. Grade 1: Mild Grade 2: Moderate Grade 3: Severe or medically significant but not immediately life threatening Grade 4: Life threatening consequences Grade 5: Death related to the adverse event | 3 years | 
| Health-related Quality of Life Using FACT-G Questionnaire (Functional Assessment of Cancer Therapy-General) | FACT-G is a measure that sums the functional well being (FWB), physical well being (PWB), the social/family well-being (S/FWB), and emotional well being (EMB) using a 5-point Likert-type response choices (0 = not at all; 1 = a little bit; 2 =somewhat; 3 = quite a bit; 4 = very much). Questions are phrased so that higher numbers indicate a better health state, leading to some items being reverse-scored. Scoring the FACT-G is performed through a simple sum of item scores with a total possible score of 105. | Baseline and 6 months | 
| Health-related Quality of Life Using EQ-5D (European Quality of Life Five Dimension) Questionnaire With VAS (Visual Analogue Scale) | EQ-5D is a standardized participant completed questionnaire consisted of 2 components: a health state profile and VAS. EQ-5D health state profile had 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each dimension has 5 levels: 1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, and 5= extreme problems. Responses to 5 dimensions comprised a health state/a single utility index value. Every health state (coded as combination of responses on each of 5 dimensions) had a unique predefined utility index value assigned to it, by EuroQol. US value sets (with all possible health states) was used for adults in the study, range from 1 to -0.109. Higher (positive) scores = better health state. VAS was used to record a participant's rating for his/her current health-related quality of life state and captured on a vertical VAS (0-100), where 0 = worst imaginable health state and 100 = best imaginable health state. | Baseline and 6 months | 
| Health-related Quality of Life Using FKSI (Functional Assessment of Cancer Therapy-Kidney Symptom Index) Questionnaire | The FKSI is a 15 question validated symptom index for kidney cancer patients. This scale focuses on symptoms predominantly related to kidney cancer such as energy, fatigue, pain, bone pain, weight loss, shortness of breath, cough, fever, hematuria. Each item was scored on a 5-point scale (0=not at all to 4=very much). FKSI total score ranged from 0 (most severe symptoms) to 60 (no symptoms) with a higher score indicating a better outcome. | Baseline and 6 months |