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Phase II

Phase II Study of Front Line Therapy With Nivolumab and Salvage Nivolumab + Ipilimumab in Patients With Advanced Renal Cell Carcinoma

  • Study HIC#:2000022534
  • Last Updated:07/15/2021

Phase II trial of nivolumab in 120 treatment naïve patients with ccRCC

  • Start Date05/26/2021
  • End Date02/01/2020

Trial Purpose and Description

Primary Outcome Measures  :

  1. Progression Free Survival (PFS) rate [ Time Frame: 1 year ]Determine the PFS rate at 1 year of nivolumab in patients with treatment naïve ccRCC based on tumor PD-L1 expression

Secondary Outcome Measures  :

  1. Progression Free Survival (PFS) rate [ Time Frame: 1 year ]Determine the PFS at 1 year of nivolumab in patients with treatment naïve ccRCC based on the PD1- Blockade Durable Response Predictive (PRP) biomarker model developed in the DFHCC Kidney Cancer SPORE
  2. Objective Response Rate (CR/PR) [ Time Frame: 1 year ]Determine the objective response rate (CR/PR) for nivolumab in patients with treatment naïve ccRCC
  3. Response Rate [ Time Frame: 1 year ]Determine the response rate of combined nivolumab and ipilimumab therapy at the time of nivolumab failure
  4. Clinical Activity (Complete Response (CR), Partial Response (PR) and Stable Disease (SD) [ Time Frame: 1 year ]Determine the clinical activity (CR, PR and SD) at 1 year of nivolumab in patients with treatment naive nccRCC
  5. Progression Free Survival (PFS) at one year [ Time Frame: 1 year ]Evaluate patients on nivolumab for progressive disease or death
  6. Toxicity by calculating the frequency and percentage of adverse event terms (CTCAE v4) [ Time Frame: 1 year ]Assess the toxicity of nivolumab monotherapy in patients with treatment naïve cc or nccRCC by calculating the frequency and percentage of adverse event terms (CTCAE v4)

Eligibility Criteria

Inclusion Criteria-Part A:

Subject must meet all of the following applicable inclusion criteria to participate in this study:

  • Patients must have histologically confirmed advanced RCC (any histology). Collecting duct tumors and tumors originating from the renal pelvis or upper urinary tract are considered of urothelial origin and are excluded from this protocol.
  • Patients must have at least one measurable site of disease, per RECIST 1.1, that has not been previously irradiated. If the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation.
  • ECOG performance status 0-2
  • Have signed the current approved informed consent form

Patients must have adequate organ function within 14 days prior to study entry as evidenced by screening laboratory values that must meet the following criteria:


  • White blood cell (WBC) ≥ 2000/µL
  • Absolute Neutrophil Count (ANC) ≥ 1500/μL
  • Platelets (Plt) ≥ 100 x103/μL
  • Hemoglobin (Hgb) > 9.0 g/dL (with or without transfusion)


  • Serum Creatinine ≤ 1.5 x ULN; if creatinine > 1.5, subject must demonstrate CrCl as outlined below.
  • Calculated creatinine clearance ≥ 40 mL/min using Cockcroft-Gault formula


  • Bilirubin ≤ 1.5× upper limit of normal (ULN); Except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL
  • Aspartate aminotransferase (AST) ≤ 3 × ULN
  • Alanine aminotransferase (ALT) ≤ 3 × ULN
  • Archival tissue is mandatory (a tumor biopsy- core or excisional) of a metastatic lesion obtained within 1 year prior to study registration (within 4 weeks preferred). Tumor tissue from nephrectomy and site of metastasis will be required. If archival tissue of a metastatic lesion obtained within the preceding year is not available, patients must have at least one site of disease (not including bone metastases) accessible for core needle or excisional biopsy. If archival tissue of a metastatic lesion is not available and biopsy of a new lesion is not feasible, the subject is not eligible for the study.
  • Patients should not have received prior systemic therapy for metastatic RCC. Prior radiotherapy must have been completed at least 2 weeks prior to the administration of study drug. Patients must be 2 weeks from prior major surgery and 1 week from pre-treatment biopsy. Prior systemic adjuvant therapy (excluding with PD1 or CTLA4 pathway blockers) is allowed if treatment completed > 12 months previously.
  • Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks
  • Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) during screening for registration purposes. This pregnancy test should be repeated within 24 hours prior to the start of nivolumab.
  • Women must not be breastfeeding
  • Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception.
  • Be willing and able to comply with this protocol.

Exclusion Criteria:

  • Patients are excluded if they have active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for 2 weeks of more after treatment is complete and within 28 days prior to the first dose of nivolumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
  • Patients with controlled brain metastases are allowed on protocol if they had solitary brain metastases that was surgically resected without recurrence or treated with SRS without progression x 4 weeks.
  • Patients should be excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have 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.
  • Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
  • As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab-containing regimen
  • Active infection requiring systemic therapy
  • Has any other medical or personal condition that, in the opinion of the site investigator, may potentially compromise the safety or compliance of the patient, or may preclude the patient's successful completion of the clinical trial
  • Patients should be excluded if they are positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
  • Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
  • Allergies and Adverse Drug Reaction
    • History of allergy to study drug components
    • History of severe hypersensitivity reaction to any monoclonal antibody
  • Known additional malignancies within the past 3 years (excluding basal of squamous cell skin cancers, CIS or localized prostate cancer that has been treated or is being observed)

Inclusion/Exclusion Criteria- Part B

  • Must meet eligibility criteria for initiation of Part A with the exception of being allowed to have prior nivolumab in Part A of this protocol
  • Must have evidence of either RECIST 1.1 defined Disease Progression or Stable Disease 1 year after initiating nivolumab therapy
  • Must undergo repeat tumor biopsy for acquisition of resistant tumor tissue
  • Must not have had a Grade ≥ 3 irAE on nivolumab monotherapy
  • Must not have untreated brain metastases
  • Must not have had major surgery or radiation therapy within 14 days of starting study treatment
  • Must not have active autoimmune disease
  • Must not have a concurrent medical condition requiring use of systemic corticosteroids with prednisone >10 mg per day
  • Must not have had prior systemic therapy for Stage IV RCC (except for nivolumab as part of part A of this protocol)
  • Prior solid organ or stem cell transplant

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