Study of Optimized Management of Nivolumab Based on Response in Patients With Advanced RCC (OMNIVORE Study)

Study Overview
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Brief Summary
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This research study is studying two drugs at different time points as a possible treatment for advanced renal cell cancer The drugs involved in this study are: Nivolumab Ipilimumab

Detailed Description
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This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of investigational drugs to learn whether the drugs work in treating a specific disease. Investigational means that the intervention is being studied. Nivolumab and ipilimumab are antibodies (a type of human protein) that work to stimulate your body's immune system to fight tumor cells. The FDA (the U.S. Food and Drug Administration) has approved nivolumab as a treatment option for this disease; however, the FDA has not approved the way nivolumab and ipilimumab are being administered in this study. Ipilimumab is FDA approved for the treatment of melanoma (skin cancer) and has been previously studied in renal cell cancer. This study is being done to evaluate nivolumab treatment strategies based on each patients individual response to treatment. In participants who have a response to treatment, nivolumab will be stopped and participants will be closely monitored. In participants who do not have a response to treatment,the investigators will investigate whether the addition of ipilimumab improves a participant response to treatment. Participant blood and tissue samples will be collected to learn about how certain biomarkers and genes relate to participant outcomes.

Official Title
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Phase II Study of Optimized Management of NIVOlumab Based on REsponse in Patients With Advanced Renal Cell Carcinoma (OMNIVORE Study)

Conditions
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Renal Cancer

Intervention / Treatment
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* Drug: Ipilimumab
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Age ≥ 18 years at the time of consent. ECOG Performance Status of ≤ 2 within 28 days prior to registration. Unresectable advanced or metastatic RCC to include both clear cell and non-clear histologies. oPatients who have suspected metastatic RCC, which has not yet been pathologically proven, may be enrolled if they plan to undergo a cytoreductive nephrectomy, metastectomy, or biopsy. Fresh tissue from one of these procedures can be used for the clinical trial requirements (eligibility #4) as well as serve as pathologic confirmation of RCC. The pathologic confirmation must be documented prior to C1D1. Availability at the study site of formalin-fixed, paraffin-embedded (FFPE) archival tumor specimens, when available, and willingness of the subject to undergo mandatory fresh tumor biopsy prior to treatment initiation unless determined medically unsafe or not feasible. If a target lesion is biopsied at screening, this lesion must be followed as non-target lesion after the biopsy unless it is the patient's only target lesion. If there is only one target lesion, it should be followed as a target lesion regardless. The archival specimen must contain adequate viable tumor tissue. The specimen may consist of a tissue block (preferred and should contain the highest grade of tumor) or at least 30 unstained serial sections. Fine-needle aspiration, brushings, cell pellet from pleural effusion, bone marrow aspirate/biopsy are not acceptable. Previously untreated or treated subjects with no limit on prior lines of systemic therapies are allowed. Patient may have received prior adjuvant therapy. Measurable disease as defined by Response Evaluation Criteria In Solid Tumors RECIST 1.1 within 28 days prior to registration. Demonstrate adequate organ function as defined in the table below. All screening labs to be obtained within 28 days prior to first study treatment. System Laboratory Value Hematological White blood cell (WBC) ≥ 2500 cells/µL Absolute Neutrophil Count (ANC) ≥ 1500 cells/µL Platelet count (plt) ≥ 100,000/ µL Hemoglobin (Hgb) ≥ 9 g/dL (transfusions allowed) Absolute lymphocyte count ≥ 500 cells/µL Renal --Serum creatinine OR Calculated creatinine clearance ≤ 1.5 x ULN ≥ 40 mL/min Cockcroft-Gault formula will be used to calculate creatinine clearance Hepatic and Other Bilirubin ≤ 1.5 × upper limit of normal (ULN) Aspartate aminotransferase (AST) ≤ 2.5 × ULN Alanine aminotransferase (ALT) ≤ 2.5 × ULN Alkaline Phosphatase ≤ 2.5 × ULN Subjects with documented liver metastases should have AST and ALT ≤ 5 x ULN. Subjects with documented liver or bone metastases should have alkaline phosphatase ≤ 5 x ULN Subjects with known Gilbert's disease should have a serum bilirubin ≤ 3 x ULN. --Albumin > 2.5 g/dL Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 × ULN (unless on prophylactic or therapeutic dosing with low molecular weight heparin) Females of childbearing potential must have a negative serum pregnancy test within 28 days prior to registration. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. Females of childbearing potential and males must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 120 days after treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method. As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study. Exclusion Criteria Subjects meeting any of the criteria below may not participate in the study: Prior use of systemic checkpoint inhibitors for the management of metastatic RCC is excluded. Prior IFN-α or IL-2 is allowed. Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitors) within 2 weeks of enrollment or receipt of any anti-cancer therapy (including investigational therapy, monoclonal antibodies, cytokine therapy) within 4 weeks of enrollment. Treatment with systemic immunosuppressive medications including but not limited to: prednisone, dexamethasone, cyclosporin, azathioprine, methotrexate, thalidomide, anti- tumor necrosis factor (TNF) agents within 2 weeks of first study dose. Subjects who have received acute, low-dose systemic immunosuppressant medications may be enrolled (such as steroids for acute nausea or cancer-related pain ≤ 10 mg prednisone) may be enrolled sooner than 2 weeks of first study dose. Subjects with adrenal insufficiency on physiologic replacement doses of steroids may be enrolled (≤ 10 mg prednisone). The use of inhaled, topical, ocular or intra-articular corticosteroids and mineralocorticoids are allowed. Treatment with a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor (e.g. denosumab) within 2 weeks of first study dose. Radiotherapy for RCC within 14 days of first study treatment with the exception of a single fraction of radiation administered for palliation of symptoms. Known active metastases to the brain, spinal cord or leptomeninges unless adequately treated with radiotherapy, radiosurgery, or surgery and stable for at least 4 weeks of first study treatment as documented by magnetic resonance imaging (MRI) or computerized tomography (CT) imaging and having no ongoing requirement for steroids. Malignancies other than RCC within 5 years of first study treatment with the exception of those with negligible risk of metastases or death and/or treated with expected curative outcome (carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, ductal carcinoma in situ of the breast, non-muscle invasive urothelial carcinoma). History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion protein. Known hypersensitivity to any component of the nivolumab or ipilimumab product. Any active or recent history (within 6 months of first study dose) of autoimmune disease or syndrome that requires systemic corticosteroids (>10 mg daily prednisone equivalent) or immunosuppressive medications including but not limited to: myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, Wegner's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Subjects with vitiligo, controlled type I diabetes mellitus, hypo- or hyperthyroid disease, or surgical adrenal insufficiency requiring hormone replacement therapy are permitted to enroll. Any condition requiring treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medication within 14 days of the first dose of study drug. Inhaled, topical, ocular or intra-articular steroids and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Uncontrolled adrenal insufficiency. History of idiopathic pulmonary fibrosis, organized pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening imaging CT of the chest. History of radiation pneumonitis in the radiation field is permitted. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome. Known active or chronic hepatitis B infection (defined as having a positive hepatitis B surface antigen (HBsAg) test at screening). Subject with past or resolved hepatitis B infection (defined as having a negative HBsAg test and positive antibody to hepatitis B core antigen test) are eligible. Hepatitis B viral DNA must be obtained in subjects with positive hepatitis B core antibody prior to first treatment start. Active hepatitis C infection. Subjects positive hepatitis C antibody test are eligible if PCR is negative for hepatitis C viral DNA. Severe infections within 4 weeks of first study treatment including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia. Receipt of therapeutic oral or IV antibiotics within 2 weeks of first study treatment. Subjects receiving routine antibiotic prophylaxis (for dental extractions/procedures) are eligible. Significant cardiovascular disease such as New York Heart Association (NYHA) class III or greater, myocardial infarction within the previous 3 months, unstable arrhythmias, unstable angina. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 45% must be on a stable regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist when appropriate. Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on screening EKG > 500 msec. History of abdominal or tracheoesophageal fistula or GI perforation within 6 months of first study treatment. Clinical signs or symptoms of GI obstruction or requirement of routine parenteral nutrition. Evidence of abdominal free air not explained by paracentesis or recent surgical procedure. Serious, non-healing or dehiscing wound or active ulcer Major surgical procedure within 4 weeks of first study treatment. Presence of any toxicities attributed to prior anti-cancer therapy that are not resolved to grade 1 (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0) or baseline before administration of study drug. Prior allogenic stem cell or solid organ transplant. Administration of a live, attenuated vaccine within 4 weeks for first study 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Overall cohort: Initial Primary Treatment with Nivolumab (induction phase)<br>Therapy with nivolumab IV every 2 weeks Serial imaging assessments every 8 weeks After confirmatory scans, patients are assigned to Arm A or Arm B. | Drug: Nivolumab<br>* Nivolumab binds to and blocks the activation of PD-1, an Ig superfamily transmembrane protein, by its ligands programmed cell death ligand 1 (PD-L1), overexpressed on certain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on APCs<br>* Other names: Opdivo;|
| Experimental: Arm A: Observation Arm (for patients with persistent response to induction nivolumab)<br>Patients with persistent response (complete or partial response) to induction nivolumab are assigned to Arm A (Observation Arm). Patients discontinued nivolumab after allocation to Arm A. Serial imaging assessments every 8 weeks. If scans persistently show PR/CR, patients remained on observation. If progressive disease develops, therapy with nivolumab (480 mg IV every 4 weeks) will be resumed. If there is subsequent progression on nivolumab monotherapy, ipilimumab (1 mg/kg IV every 3 weeks x 2 doses) is added. If progression after nivolumab + ipilimumab, therapy discontinued. If SD/PR/CR, nivolumab is continued until progression. | Drug: Ipilimumab<br>* YERVOY is thought to work with the body's immune system to increase the activity of T cells and cause the body to attack cancer cells<br>* Other names: Yervoy;Drug: Nivolumab<br>* Nivolumab binds to and blocks the activation of PD-1, an Ig superfamily transmembrane protein, by its ligands programmed cell death ligand 1 (PD-L1), overexpressed on certain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on APCs<br>* Other names: Opdivo;|
| Experimental: Arm B: Nivolumab+Ipilimumab then nivolumab alone (for patients with SD/PD to induction nivolumab)<br>Patients with confirmed SD/PD to induction nivolumab are allocated to Arm B (Combination Therapy Arm). In combination therapy, patients received nivolumab 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for two doses. After then nivolumab will be continued at 480 mg IV every 4 weeks until disease progression. Arm B patients undergo imaging at 12 weeks and then every 8 weeks. | Drug: Ipilimumab<br>* YERVOY is thought to work with the body's immune system to increase the activity of T cells and cause the body to attack cancer cells<br>* Other names: Yervoy;Drug: Nivolumab<br>* Nivolumab binds to and blocks the activation of PD-1, an Ig superfamily transmembrane protein, by its ligands programmed cell death ligand 1 (PD-L1), overexpressed on certain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on APCs<br>* Other names: Opdivo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With Persistent Partial Response (PR) or Complete Response (CR) at 1 Year Since Nivolumab Discontinuation (Arm A Only) | Persistent PR or CR is defined per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 guidelines. Radiologic disease assessment was performed every 8 weeks after patients discontinued nivolumab induction therapy. At 1 year after nivolumab discontinuation, the percentage of patients with persistent PR and CR were reported (for Arm A only). | From nivolumab discontinuation until 1 year after discontinuation with nivolumab | 
| Percentage of Subjects With Stable or Progressive Disease (SD/PD) to Nivolumab Induction That Convert to Complete or Partial Response (CR/PR) Upon the Addition of Ipilimumab to Nivolumab (Arm B Only) | Response is defined per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 guideline. After initiation of ipilimumab, Arm B patients underwent imaging after the first 12 weeks and then every 8 weeks until disease progression. Best overall response during Arm B treatment were summarized with 90% confidence interval. | For arm B patients, from arm B treatment (nivolumab+ipilimumab) initiation until last imaging assessment during the treatment; assessed up to 22 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression Free Survival (Arm B) | Progression-free survival (PFS) for Arm B was defined as time from the start of arm B treatment until progression (by RECIST 1.1 or clinical PD) or death from any cause or censored at date of last disease evaluation for those who are alive and have not progressed. PFS distribution was estimated using the product-limit method of Kaplan-Meier, median and 95% confidence interval was reported. | After initiation of Arm B treatment, patients underwent imaging at 12 weeks and then every 8 weeks, up to 22 months. | 
| 18-month Overall Survival Rate From Initiation of Nivolumab Induction (Overall Cohort) | Overall survival (OS) was defined as the time from initiation of nivolumab induction until death due to any cause or censored at date of last follow-up for surviving patients. OS rate was estimated using the product-limit method of Kaplan-Meier;18-month OS rate and 95% confidence interval were reported. | Patients were followed from initiation of Nivolumab induction until to death or date last known alive. Kaplan-Meier curve for OS assessed up to 28 months; the 18-month time point estimate for OS was reported. | 
| Percent of Subjects Who Were Free of Nivolumab Salvage Therapy at 1 Year Since Discontinuation of Nivolumab Induction (Arm A) | Number and proportion of arm A patients who remained free of nivolumab treatment at 1 year since discontinuation of nivolumab induction | For arm A, from nivolumab discontinuation until 1 year after discontinuation with nivolumab | 
| Immune Related Objective Response Rate (irORR) in Arm A and Arm B | The irORR is assessed according to immune-related Response Criteria (irRC). Immune-Related Complete Response (irCR): Complete disappearance of all tumor lesions (index and non-index together with no new measurable/unmeasurable lesions) for at least 4 weeks from the date of documentation of complete response Decrease, relative to baseline, of 50% or greater in the sum of the products of the two largest perpendicular diameters (SPD) of all target and all new measurable lesions in two consecutive observations not less than 4 weeks apart. | For arm A, radiology imaging will be done every 8 weeks until disease progression. For arm B, radiology imaging will be done at 12 weeks and then every 8 weeks until disease progression | 
| Percentage of Subjects Who Experience Grade 3-4 Treatment-related Adverse Event (TRAE) During the Nivolumab Induction Therapy (Overall Cohort) | Adverse event was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4. The following AE attribution was considered as treatment-related: Definite - The AE is clearly related to the study treatment. Probable - The AE is likely related to the study treatment. Possible - The AE may be related to the study treatment. | Adverse events during the nivolumab induction were measured from nivolumab initiation until 3 months following the last dose of nivolumab induction or until start of arm B treatment, assessed up to 9 months from nivolumab start | 
| Percentage of Subjects Who Experienced Grade 3-4 Treatment Related Adverse Events (TRAE) During the Arm B Treatment (Arm B Only) | Adverse event was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4. The following AE attribution was considered as treatment-related: Definite - The AE is clearly related to the study treatment. Probable - The AE is likely related to the study treatment. Possible - The AE may be related to the study treatment. | For arm B, adverse events were measured from arm B treatment initiation until 3 months following the last dose of arm B treatment, assessed up to 26 months from arm B start | 
| Percentage of Subjects Who Had Complete or Partial Response (CR/PR) to Nivolumab Induction Therapy According to International mRCC Database Consortium (IMDC) Risk Groups. | Response (PR or CR) is defined per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 guidelines. Radiologic disease assessment was performed every 8 weeks during the induction therapy with nivolumab. | From start of nivolumab induction until the discontinuation of nivolumab induction, assessed up to 7 months | 
| Percentage of Subjects Who Had Complete or Partial Response (CR/PR) to Nivolumab Induction Therapy According to Prior Treatment | Response (PR or CR) is defined per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 guidelines. Radiologic disease assessment was performed every 8 weeks during the induction therapy with nivolumab. | From start of nivolumab induction until the discontinuation of nivolumab induction, assessed up to 7 months | 
| Percentage of Subjects Who Had Complete or Partial Response (CR/PR) to Nivolumab Induction Therapy According to Histology Type | Response (PR or CR) is defined per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 guidelines. Radiologic disease assessment was performed every 8 weeks during the induction therapy with nivolumab. | From start of nivolumab induction until the discontinuation of nivolumab induction, assessed up to 7 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal Cancer