Nivolumab with or without Ipilimumab after Initial Nivolumab Treatment in Treating Patients with Kidney Cancer That Is Advanced, Metastatic, or Cannot Be Removed by Surgery
This randomized phase II trial studies how well nivolumab with or without ipilimumab after initial nivolumab treatment works in treating patients with kidney cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment, or that cannot be removed by surgery. Monoclonal antibodies, such as nivolumab and ipilimumab, may interfere with the ability of tumor cells to grow and spread. Giving ipilimumab in addition to nivolumab may work better in treating patients without a disease response after initial treatment with nivolumab only.
- Eastern Cooperative Oncology Group (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 * Patients 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 as well as serve as pathologic confirmation of RCC; the pathologic confirmation must be documented prior to course 1 day 1 (C1D1) * Single cell sequencing cohort only: histology must have predominant clear cell component
- 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; 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/biopsy, brushings, cell pellet from pleural effusion, bone lesion, 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 * Single cell sequencing cohort only: must have had no prior systemic therapy for RCC, or maximum of 1 prior tyrosine kinase inhibitor (TKI)-based regimen for RCC; levatinib + everolimus counts as 1 regimen
- Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 within 28 days prior to registration
- White blood cell (WBC) >= 2500 cells/uL (obtained within 28 days prior to first study treatment)
- Absolute neutrophil count (ANC) >= 1500 cells/uL (obtained within 28 days prior to first study treatment)
- Platelet count (plt) >= 100,000/ uL (obtained within 28 days prior to first study treatment)
- Hemoglobin (Hgb) >= 9 g/dL (obtained within 28 days prior to first study treatment)
- Absolute lymphocyte count >= 500 cells/uL (obtained within 28 days prior to first study treatment)
- Serum creatinine =< 1.5 x upper limit of normal (ULN) OR calculated creatinine clearance >= 40 mL/min (obtained within 28 days prior to first study treatment) * Cockcroft-Gault formula will be used to calculate creatinine clearance
- Bilirubin =< 1.5 x upper limit of normal (ULN) (obtained within 28 days prior to first study treatment) * Subjects with known Gilbert’s disease should have a serum bilirubin =< 3 x ULN
- Aspartate aminotransferase (AST) =< 2.5 x ULN (obtained within 28 days prior to first study treatment) * Subjects with documented liver metastases should have AST =< 5 x ULN
- Alanine aminotransferase (ALT) =< 2.5 x ULN (obtained within 28 days prior to first study treatment) * Subjects with documented liver metastases should have ALT =< 5 x ULN
- Alkaline phosphatase =< 2.5 x ULN (obtained within 28 days prior to first study treatment) * Subjects with documented liver or bone metastases should have alkaline phosphatase =< 5 x ULN
- Albumin > 2.5 g/dL (obtained within 28 days prior to first study treatment)
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN (unless on prophylactic or therapeutic dosing with low molecular weight heparin, or oral anticoagulants (e.g. coumadin, rivaroxaban) (obtained within 28 days prior to first study treatment)
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN (unless on prophylactic or therapeutic dosing with low molecular weight heparin, or oral anticoagulants (e.g. coumadin, rivaroxaban) (obtained within 28 days prior to first study treatment)
- 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 150 days after treatment discontinuation for females and 210 days after treatment discontinuation for males; 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
- Prior use of systemic checkpoint inhibitors for the management of metastatic RCC is excluded; prior IFN-alpha or IL-2 is allowed
- Single cell sequencing cohort only: non-clear cell histology
- 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) 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 (included but not limited to 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, Wegener’s granulomatosis, Sjogren’s syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis; subjects with vitiligo, controlled type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only 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 deoxyribonucleic acid (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 polymerase chain reaction (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 electrocardiogram (EKG) > 500 msec
- History of abdominal or tracheoesophageal fistula or gastrointestinal (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
Locations & Contacts
Contact: Rana Ramzi McKay
Contact: Walter M. Stadler
Contact: Walter M. Stadler
Contact: Walter M. Stadler
Contact: David F. McDermott
Contact: Lauren Christine Harshman
Contact: Lauren Christine Harshman
Contact: Tracy L. Rose
Contact: Benedito Arruda Carneiro (Filho)
Salt Lake City
Contact: Neeraj Agarwal
Contact: Christos Kyriakopoulos
Trial Objectives and Outline
I. Assess the proportion of subjects with persistent complete response (CR) or partial response (PR) at one year after nivolumab discontinuation. (Arm A)
II. Assess the proportion of subjects with progressive disease (PD)/stable disease (SD) that convert to PR/CR at one year upon the addition of ipilimumab to nivolumab. (Arm B)
I. Assess progression-free survival (PFS) and overall survival (OS) rates in Arm A and Arm B.
II. To assess the rate of re-initiation of nivolumab (salvage) therapy. (Arm A)
III. Assess the immune-related ORR (irORR) in subjects in Arm A and B.
IV. Assess safety and toxicity in study arms A and B.
V. Summarize PR/CR rate, PFS, and OS in the overall cohort and by each arm according to subgroups: 1) International metastatic renal cell carcinoma (mRCC) Database Consortium (IMDC) risk groups; 2) Untreated versus previously treated subjects; 3) Histologic subtype (clear cell versus non-clear cell renal cell carcinoma [RCC] subtypes; sarcomatoid components present versus absent).
I. Evaluate the relationship between tumor-infiltrating lymphocytes (TILs), programmed death-ligand 1 (PD-L1) tumor expression, and other tissue biomarkers with efficacy outcomes (proportion of PR/CR, PFS, OS).
II. Evaluate the relationship between PD-L1 status in archival tissue and in fresh tumor specimens.
III. Evaluate mechanisms of response to nivolumab in fresh tumor specimens obtained at baseline in subjects with a durable response to treatment (>= 1 year).
IV. Evaluate mechanisms of intrinsic and acquired resistance to nivolumab and ipilimumab treatments in fresh tumor specimens obtained at time of radiographic progression.
V. Assess molecular mechanisms of resistance to treatment via circulating free deoxyribonucleic acid (DNA) (cfDNA) assessment and to correlate cfDNA molecular profile with metastasis biopsy molecular profile.
VI. Assess molecular mechanisms of resistance to treatment via circulating tumor cell (CTC) assessment
VII. Correlate CTC molecular profile with metastasis biopsy molecular profile.
VIII. Assess mechanisms of response and resistance to treatment via single cell molecular assessment (transcriptome assessment).
IX. Correlate single cell molecular profile with metastasis biopsy molecular profile.
PRIMARY TREATMENT: All patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients with CR or PR after the first 2 courses continue nivolumab for an additional 2 courses in the absence of unacceptable toxicity. Patients with stable disease (SD) after the first 2 courses continue nivolumab for another 2 courses, and then, if these patients achieve CR or PR after the second 2 courses, they then continue nivolumab for an additional 2 courses in the absence of unacceptable toxicity.
RESPONSE AFTER PRIMARY TREATMENT: Patients are assigned to 1 of 2 arms.
ARM A (CR OR PR AFTER PRIMARY TREATMENT): Patients discontinue nivolumab and undergo observation. If PD is documented, patients receive nivolumab IV over 30 minutes on day 1. Courses repeat every 28 days in the absence of PD or unacceptable toxicity. If PD is documented after re-initiation of nivolumab, patients then receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on days 1 and 22. Treatment repeats every 3 weeks for up to 2 courses in the absence of unacceptable toxicity. Patients then continue nivolumab on day 1. Courses repeat every 28 days in the absence of PD or unacceptable toxicity.
ARM B (SD OR PD AFTER PRIMARY TREATMENT): Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Courses repeat every 3 weeks in the absence of PD or unacceptable toxicity. Patients with SD, CR, or PR after first 2 courses then continue nivolumab on day 1. Courses repeat every 28 days in the absence of PD or unacceptable toxicity.
After completion of treatment, patients are followed up at 30 and 100 days, and then every 6 months for 2 years.
Trial Phase & Type
Dana-Farber Harvard Cancer Center
Lauren Christine Harshman
Secondary IDs NCI-2017-02334
Clinicaltrials.gov ID NCT03203473