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

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ClinicalTrials.gov Identifier: NCT03203473
Recruitment Status : Recruiting
First Posted : June 29, 2017
Last Update Posted : July 16, 2018
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Lauren C. Harshman, Dana-Farber Cancer Institute

Brief Summary:

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


Condition or disease Intervention/treatment Phase
Renal Cancer Drug: Ipilimumab Drug: Nivolumab Phase 2

Detailed Description:

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 58 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of Optimized Management of NIVOlumab Based on REsponse in Patients With Advanced Renal Cell Carcinoma (OMNIVORE Study)
Actual Study Start Date : September 26, 2017
Estimated Primary Completion Date : November 30, 2020
Estimated Study Completion Date : November 30, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Cancer

Arm Intervention/treatment
Experimental: Initial Primary Treatment
  • 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
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
Other Name: Opdivo

Experimental: Arm A: Persistent (PR/CR)
  • Serial imaging assessments every 8 weeks
  • Therapy with nivolumab IV every 2 weeks
  • If scans persistently show PR/CR, nivolumab is discontinued until progression.
  • Nivolumab is re-initiated, and if there is subsequent progression, ipilimumab is added for x2 doses.
  • Ipilimumab IV every 3 weeks (only in patients who progress after nivolumab re-initiation)
  • If progression after nivolumab + ipilimumab, therapy discontinued. If SD/PR/CR, nivolumab is continued until progression.
Drug: Ipilimumab
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
Other Name: Yervoy

Drug: Nivolumab
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
Other Name: Opdivo

Experimental: Arm B: Persistent (PD/SD)
  • Therapy with nivolumab IV every 2 weeks
  • Ipilimumab IV every 3 weeks
  • Serial imaging assessments every 8 week
  • If scans show SD/PR/CR, nivolumab continued until progression. If progression, therapy discontinued.
Drug: Ipilimumab
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
Other Name: Yervoy

Drug: Nivolumab
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
Other Name: Opdivo




Primary Outcome Measures :
  1. Number of subjects with persistent Partial Response (PR) or Complete Response (CR) at 1 year since nivolumab discontinuation (Arm A) [ Time Frame: 1 year after discontinuation with nivolumab ]
    Persistent PR or CR is defined as radiologic disease assessment performed every 8 weeks since primary nivolumab therapy. These radiologic disease assessments are evaluated per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 guidelines. At 1 year after nivolumab discontinuation, the proportion of patients with persistent PR and CR will be evaluated by established methods (for Arm A only).

  2. Number of subjects with Progressive Disease (PD) or Stable Disease (SD) that convert to PR or CR at 1 year upon the addition of ipilimumab to nivolumab (Arm B) [ Time Frame: 1 year after addition of ipilimumab to nivolumab ]
    PD or SD is defined as radiologic disease assessment performed every 8 weeks since primary nivolumab therapy. Confirmatory scans will be performed at 4 and 8 weeks, respectively for PD and SD evaluation. If persistent, ipilimumab will be added to nivolumab treatment and scans will continue every 12 weeks for assessment. These radiologic disease assessments are evaluated per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 guidelines. At 1 year after nivolumab discontinuation, the proportion of patients with PD or SD will be evaluated by established methods (for Arm B only).


Secondary Outcome Measures :
  1. Progression Free Survival [ Time Frame: Disease will be evaluated every 8 or 12 weeks (depending on treatment) from study entry until disease progression, up to 24 months. ]
    The progression-free survival (PFS) rates for Arms A and B will each be summarized using the product-limit method of Kaplan-Meier. PFS is defined as the time from nivolumab discontinuation (Arm A) or from ipilimumab initiation (Arm B) until documented progression by RECIST version 1.1 criteria or death from any cause, censored at date last known progression-free for those who are alive and have not progressed.

  2. Overall Survival [ Time Frame: Patients will be followed from study entry to death or date last known alive, assessed up to 36 months. ]
    The overall survival (OS) rates for Arms A and B will each be summarized using the product-limit method of Kaplan-Meier. OS is defined as the time from nivolumab discontinuation (Arm A) or from ipilimumab initiation (Arm B) until death from any cause, censored at date last known alive or at the time of last assessment of follow-up.

  3. Salvage therapy-free interval [ Time Frame: On Arm A, the time from nivolumab discontinuation to the receipt of re-starting nivolumab, on average about 12 months. ]
    The salvage therapy rate is defined as time from nivolumab discontinuation (arm A) to the receipt of re-starting nivolumab.

  4. Immune related objective response rate (irORR) [ Time Frame: Disease will be evaluated every 8 or 12 weeks (depending on treatment) from study entry until disease progression per irORR criteria, up to 24 months. ]
    The irORR) in subjects in Arms A and B is defined according to immune-related Response Criteria (irRC) and will be estimated using exact binomial methods.

  5. Safety and tolerability according to Common Terminology Criteria for Adverse Events (CTCAE) version 4. [ Time Frame: Throughout the course of the study, approximately 24 months after study entry ]
    In both Arms A and B, all adverse events recorded during the trial will be summarized for the safety population.The incidence of events that are new or worsening from the time of first dose of treatment will be summarized according to system organ class and/or preferred term, severity (based on CTCAE version 4), type of adverse event, and relation to study treatment.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03203473


Contacts
Contact: Lauren C Harshman, MD 617-632-4524 LaurenC_Harshman@DFCI.HARVARD.EDU

Locations
United States, California
University of California, San Diego Moores Cancer Center Recruiting
La Jolla, California, United States, 92093
Contact: Rana McKay, MD       rmckay@ucsd.edu   
Principal Investigator: Rana McKay, MD         
United States, Illinois
University of Chicago Medical Center Recruiting
Chicago, Illinois, United States, 60637
Contact: Walter Stadler, MD       Wstadler@medicine.bsd.uchicago.edu   
Principal Investigator: Walter Stadler, MD         
United States, Massachusetts
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02115
Contact: David F McDermott, MD    617-632-9250      
Principal Investigator: David F McDermott, MD         
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
Contact: Lauren C Harshman, MD    617-632-4524    LaurenC_Harshman@DFCI.HARVARD.EDU   
Principal Investigator: Lauren C Harshman, MD         
United States, North Carolina
University of North Carolina at Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Tracy Rose, MD       tracy_rose@med.unc.edu   
Principal Investigator: Tracy Rose, MD         
United States, Rhode Island
Lifespan Comprehensve Cancer Center Recruiting
Providence, Rhode Island, United States, 02903
Contact: Benedito Carneiro, MD       Benedito.Carneiro@Lifespan.org   
Principal Investigator: Benedito Carneiro, MD         
United States, Utah
University of Utah, Huntsman Cancer Center Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Neeraj Agarwal, MD       Neeraj.Agarwal@hci.utah.edu   
Principal Investigator: Neeraj Agarwal, MD         
United States, Wisconsin
Unviersity of Wisconsin Carbone Cancer Center Recruiting
Madison, Wisconsin, United States, 53792
Contact: Christos Kyriakopoulo, MD       ckyriako@medicine.wisc.edu   
Principal Investigator: Christos Kyriakopoulo, MD         
Sponsors and Collaborators
Dana-Farber Cancer Institute
Bristol-Myers Squibb
Investigators
Principal Investigator: Lauren C Harshman, MD Dana-Farber Cancer Institute

Responsible Party: Lauren C. Harshman, Assistant Professor of Medicine, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT03203473     History of Changes
Other Study ID Numbers: 17-064
First Posted: June 29, 2017    Key Record Dates
Last Update Posted: July 16, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Lauren C. Harshman, Dana-Farber Cancer Institute:
Renal Cancer

Additional relevant MeSH terms:
Kidney Neoplasms
Carcinoma, Renal Cell
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Kidney Diseases
Urologic Diseases
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Nivolumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs