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

NCT03117309

Description:

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

Related Conditions:
  • Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Front Line Therapy With Nivolumab and Salvage Nivolumab + Ipilimumab in Patients With Advanced Renal Cell Carcinoma
  • Official Title: Phase II Study of Front Line Therapy With Nivolumab and Salvage Nivolumab + Ipilimumab in Patients With Advanced Renal Cell Carcinoma. HCRN: GU16-260

Clinical Trial IDs

  • ORG STUDY ID: HCRN GU16-260
  • NCT ID: NCT03117309

Conditions

  • Advanced Renal Cell Carcinoma

Interventions

DrugSynonymsArms
Nivolumab 240 mgOPDIVOPART A: Nivolumab
Ipilimumab 1mg/kgYervoyPART B: Nivolumab + Ipilimumab
Nivolumab 3mg/kgOPDIVOPART B: Nivolumab + Ipilimumab
Nivolumab 360mgOPDIVOPART A: Nivolumab

Purpose

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

Detailed Description

      Eligible patients with biopsiable (biopsied) disease will receive nivolumab 240 mg IV every 2
      weeks x 6 doses then 360 mg every 3 weeks for up to 84 weeks. Tumor response will be assessed
      at weeks 12, 18 and 24 and then every 12 weeks. For patients who experience RECIST 1.1
      defined PD, but remain clinically stable (and asymptomatic), a confirmatory scan after 6
      weeks (± 1 week) of additional therapy is suggested. Patients with persistent PD at
      confirmatory scan will be evaluated for enrollment on Part B of this study. Symptomatic
      patients may be evaluated for Part B immediately. Patients without confirmed PD can continue
      on nivolumab therapy.

      Patients who experience symptomatic or confirmed PD (or have best response of SD at 12
      months) on nivolumab monotherapy will be eligible for consideration for Part B. Part B
      involves the addition of ipilimumab for up to 4 doses while maintaining nivolumab therapy.
      Dose of ipilimumab will be 1 mg/kg every 3 weeks together with nivolumab changed to 3 mg/kg
      every 3 weeks for up to 4 doses. Nivolumab will revert to 360 mg every 3 weeks after the
      completion of treatment with ipilimumab (beginning week 13-19 of Part B) for up to 48 weeks.
      Patients will be followed with serial imaging assessments weeks 12, 18 and 24 and then every
      12 weeks after the initiation of ipilimumab. The tumor measurements at the time of ipilimumab
      institution will be the new baseline. If unequivocal symptomatic or confirmed new PD (as
      defined above) develops, treatment will be discontinued.

      Patients for Part B must still meet the eligibility criteria for initial study enrollment.
      Patients with Grade 3 toxicity on nivolumab monotherapy, serious symptomatic disease that in
      the opinion of the site investigator requires immediate use of an alternative treatment
      approach or continued PR/CR will be excluded from enrolling in Part B. It is estimated that
      roughly half of the patients accrued to the first-line treatment will go on to enroll in Part
      B.

      An additional biopsy will be performed of a metastatic lesion at time of confirmed PD in all
      patients enrolling in Part B. Confirmation of tumor in the biopsy specimen must occur prior
      to initiation of treatment on Part B. FFPE and frozen tissue will be stored from this sample
      and used for correlative studies described below.

      An additional cohort of 40 non-ccRCC patients will be enrolled and analyzed separately for
      evidence of anti-tumor activity (CR, PR and SD and PFS at 1 year of nivolumab). These
      patients will also be eligible for participation in Part B. We anticipate that the accrual of
      these 40 patients will be able to be completed within the 1.5 years needed for accrual of the
      ccRCC patients.

      Part A: Nivolumab Administration. Nivolumab will be given every 2 weeks x 6 at a dose of 240
      mg Intravenously (IV) and then every 3 weeks at a dose of 360 mg IV until toxicity, complete
      response, disease progression, SD at 12 months or a maximum of 96 total weeks (12 weeks
      induction, 84 weeks maintenance) Patients with disease progression (at any time) or SD at 12
      months will be eligible to be considered for participation in Part B of the study.

      Part B: Nivolumab + Ipilimumab. Patients with Grade 3 toxicity on nivolumab monotherapy,
      (excluding endocrine toxicity), serious symptomatic disease that in the opinion of the site
      investigator requires immediate use of an alternative treatment approach or continued PR/CR
      will be excluded from enrolling in Part B. It is estimated that roughly half of the patients
      accrued to the first line treatment will go on to enroll in Part B.

      Ipilimumab will be given 1 mg/kg every 3 weeks together with nivolumab 240 mg every 3 weeks
      for up to 4 doses. Nivolumab will revert to 3 mg/kg every 3 weeks after the completion of
      combination treatment with ipilimumab .

      Following the first 4 doses of the combination of nivolumab and ipilimumab, nivolumab
      monotherapy will again be given every 3 weeks at a dose of 360 mg for a maximum of 48 weeks.
      Patients may be dosed no less than 18 days from the previous dose of drug; and dosed up to 3
      days after the scheduled date, if necessary.
    

Trial Arms

NameTypeDescriptionInterventions
PART A: NivolumabExperimentalNivolumab 240mg; Nivolumab 360mg
  • Nivolumab 240 mg
  • Nivolumab 360mg
PART B: Nivolumab + IpilimumabExperimentalNivolumab 3mg/kg and Ipilimumab 1mg/kg; Nivolumab 360mg
  • Ipilimumab 1mg/kg
  • Nivolumab 3mg/kg
  • Nivolumab 360mg

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:

        Hematological:

          -  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)

        Renal:

          -  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

        Hepatic:

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

Measure:Progression Free Survival (PFS) rate
Time Frame:1 year
Safety Issue:
Description: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
Measure:Objective Response Rate (CR/PR)
Time Frame:1 year
Safety Issue:
Description:Determine the objective response rate (CR/PR) for nivolumab in patients with treatment naïve ccRCC
Measure:Response Rate
Time Frame:1 year
Safety Issue:
Description:Determine the response rate of combined nivolumab and ipilimumab therapy at the time of nivolumab failure
Measure:Clinical Activity (Complete Response (CR), Partial Response (PR) and Stable Disease (SD)
Time Frame:1 year
Safety Issue:
Description:Determine the clinical activity (CR, PR and SD) at 1 year of nivolumab in patients with treatment naive nccRCC
Measure:Progression Free Survival (PFS) at one year
Time Frame:1 year
Safety Issue:
Description:Evaluate patients on nivolumab for progressive disease or death
Measure:Toxicity by calculating the frequency and percentage of adverse event terms (CTCAE v4)
Time Frame:1 year
Safety Issue:
Description: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)

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Michael B. Atkins, MD

Trial Keywords

  • Nivolumab
  • Ipilimumab
  • OPDIVO
  • IgG1 kappa immunoglobulin

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