Clinical Trials /

Intermittent Therapy in Metastatic Renal Cell Carcinoma Patients Treated With Ipilimumab and Nivolumab

NCT03126331

Description:

This study is being done with patients with advanced kidney cancer (also called renal cell carcinoma or RCC). This is a research study involving the use of the drug Nivolumab (also known as Opdivo®). Nivolumab is an anti-PD-1 antibody. It works by attaching to and blocking a molecule called PD-1. PD-1 is a protein that is present on different types of cells in the immune system and controls parts of the immune system by shutting it down. Antibodies that block PD-1 can potentially prevent PD-1 from shutting down the immune system, thus allowing it to recognize and help destroy cancer cells. In many countries (including the United States, European Union and Japan) Nivolumab is approved to treat certain cancer types. The purpose of the study is to test the safety and effectiveness of nivolumab in patients with advanced RCC when given intermittently. Nivolumab is approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced kidney cancer, non small cell lung cancer, classical Hodgkin Lymphoma and Metastatic Melanoma. Nivolumab is FDA-approved for advanced RCC because has been shown to shrink RCC tumors that have spread outside the kidney.

Related Conditions:
  • Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Intermittent Therapy in Metastatic Renal Cell Carcinoma Patients Treated With Ipilimumab and Nivolumab
  • Official Title: A Single-arm Phase II Trial of Intermittent Nivolumab in Patients With Metastatic Renal Cell Carcinoma Who Have Received Prior Anti-Angiogenic Therapy

Clinical Trial IDs

  • ORG STUDY ID: CASE5816
  • NCT ID: NCT03126331

Conditions

  • Metastatic Renal Cell Carcinoma

Interventions

DrugSynonymsArms
NivolumabOpdivo®Cohort I: Intermittent Nivolumab
IpilimumabCohort II: combination ipilimumab/nivolumab

Purpose

This study is being done with patients with advanced kidney cancer (also called renal cell carcinoma or RCC). This is a research study involving the use of the drug Nivolumab (also known as Opdivo®). Nivolumab is an anti-PD-1 antibody. It works by attaching to and blocking a molecule called PD-1. PD-1 is a protein that is present on different types of cells in the immune system and controls parts of the immune system by shutting it down. Antibodies that block PD-1 can potentially prevent PD-1 from shutting down the immune system, thus allowing it to recognize and help destroy cancer cells. In many countries (including the United States, European Union and Japan) Nivolumab is approved to treat certain cancer types. The purpose of the study is to test the safety and effectiveness of nivolumab in patients with advanced RCC when given intermittently. Nivolumab is approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced kidney cancer, non small cell lung cancer, classical Hodgkin Lymphoma and Metastatic Melanoma. Nivolumab is FDA-approved for advanced RCC because has been shown to shrink RCC tumors that have spread outside the kidney.

Detailed Description

      Primary Objective:

      - To determine the feasibility of intermittent nivolumab therapy in patients with metastatic
      renal cell carcinoma.

      Secondary Objectives:

        -  To determine the clinical outcome (overall response rate (ORR), progressive free
           survival (PFS), overall survival (OS)) in metastatic renal cell carcinoma patients
           treated with intermittent nivolumab therapy.

        -  To evaluate the toxicity of intermittent nivolumab therapy in patients with metastatic
           renal cell carcinoma.

      Correlative Objective

      - Investigate correlations between baseline and post-treatment immunomodulatory cells
      [specifically, myeloid-derived suppressor cells (MDSC) regulatory T cells (Treg), cluster of
      differentiation 4 (CD4) and cluster of differentiation 8 (CD8), T Cells, T-cell receptor
      (TCR) repertoire and time off therapy.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort I: Intermittent NivolumabExperimentalNivolumab monotherapy. Participants who have initial 10% or greater tumor burden reduction will discontinue nivolumab until they experience a pre-specified disease progression at which time nivolumab will be restarted
  • Nivolumab
Cohort II: combination ipilimumab/nivolumabExperimentalCombination of ipilimumab/nivolumab for previously untreated intermediate and poor risk mRCC Includes participants treated front-line ipilimumab/nivolumab. Participants with treatment-naïve mRCC who receive up to four doses of induction ipilimumab/nivolumab and 24 weeks (+/- 8 weeks; minimum 3 infusions) of maintenance nivolumab and achieve stable disease (SD), complete response (CR), or partial response (PR) will be eligible for inclusion. Participants who achieve SD will continue with nivolumab maintenance per standard of care while those who achieve a PR or CR will enter an observation period off therapy. Upon disease progression, participants will be re-challenged with combination ipilimumab/nivolumab.
  • Nivolumab
  • Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

          -  Cohort 1:

               -  Must have received at least one but not more than two prior anti-angiogenic
                  therapy regimens (including, but not limited to, sunitinib, sorafenib, pazopanib,
                  axitinib, tivozanib, and bevacizumab) in the advanced or metastatic RCC setting.
                  Prior cytokine therapy (eg, IL-2, IFN-a), vaccine therapy, or treatment with
                  cytotoxics is also allowed.

               -  No more than three total prior systemic treatment regimens in the advanced or
                  metastatic RCC setting.

          -  Cohort 2:

             --Achieved SD, PR, or CR after administration of front-line therapy with Ipi/Nivo (up
             to 4 doses) for advanced/metastatic RCC followed by 24 weeks (+/- 8 weeks; minimum 3
             infusions) of Nivo maintenance. Patient enrollment will occur after completion of 24
             weeks (+/- 8 weeks; minimum 3 infusions) of maintenance nivolumab.

          -  Histological confirmation of renal cell carcinoma (RCC) (any histology)

          -  Advanced or metastatic RCC.

          -  Measurable disease as defined by RECIST 1.1 criteria

          -  Must have received at least one but not more than two prior anti-angiogenic therapy
             regimens (including, but not limited to, sunitinib, sorafenib, pazopanib, axitinib,
             tivozanib, and bevacizumab) in the advanced or metastatic RCC setting. Prior cytokine
             therapy (for example, Interleukin (IL)-2, interferon (IFN)-α), vaccine therapy, or
             treatment with cytotoxics is also allowed.

          -  Patients treated with neoadjuvant and/or adjuvant therapy prior to development of
             metastatic disease may also be included provided that at least 12 months have elapsed
             since last dose. These regimens do not count toward total number of prior therapies
             permitted for trial inclusion.

          -  No more than three total prior systemic treatment regimens in the advanced or
             metastatic RCC setting, and must have evidence of progression on or after the last
             treatment regimen received and within 6 months prior to study enrollment.

          -  Karnofsky Performance Score (KPS) ≥70%

          -  Women of childbearing potential (WOCBP) must use effective method(s) of contraception
             have a negative serum or urine pregnancy test within 24 hours prior to the start of
             therapy, and must not be breastfeeding. Pregnant women are excluded from this study
             because animal studies have demonstrated that nivolumab can cause fetal harm when
             administered to pregnant women. Breastfeeding women are excluded from this study
             because nivolumab may be excreted in human milk and the potential for serious adverse
             reactions in nursing infants.

          -  Men who are sexually active with WOCBP must use any contraceptive method with a
             failure rate of less than 1% per year

          -  Willing and able to provide informed consent.

          -  Laboratory criteria for study entry must meet the following criteria:

               -  Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance
                  (CrCl) ≥ 40 mL/min (measured or calculated using the Cockcroft-Gault formula).

               -  white blood cell count ≥ 2000/µL

               -  Neutrophils ≥ 1500/µL

               -  Platelets ≥ 100,000/µL

               -  Hemaglobin ≥ 9.0g/dL

               -  Aspartate Aminotransferase (AST) and alanine transaminase (ALT) ≤ 3.0 x ULN

               -  Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total
                  bilirubin < 3.0 mg/dL)

        Exclusion Criteria:

          -  Cohort 1 only:

             --Prior treatment with an anti-programmed death (PD)-1, anti-programmed death ligand 1
             (PD-L1), anti-programmed death ligand 2 (PD-L2), anti-Cluster of differentiation
             (CD137), or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, or any
             other antibody or drug specifically targeting T-cell co-stimulation or checkpoint
             pathways.

          -  Anti-cancer therapy less than 14 days prior to the first dose of study drug (less than
             28 days for bevacizumab) or palliative, focal radiation therapy less than 14 days
             prior to the first dose of study drug.

          -  History of severe hypersensitivity reaction to any monoclonal antibody.

          -  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 imaging evidence of progression for 28 days after treatment is
             complete and within 28 days prior to the first dose of nivolumab administration.

          -  Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study
             drug.

          -  Any active known or suspected autoimmune disease. Subjects with vitiligo, type I
             diabetes mellitus, residual hypothyroidism due to autoimmune condition or prior
             therapy requiring hormone replacement, psoriasis not requiring systemic treatment, or
             conditions not expected to recur in the absence of an external trigger are permitted
             to enroll.

          -  Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily
             prednisone equivalent) or other immunosuppressive medications within 14 days prior to
             the first dose of study drug. Inhaled steroids and adrenal replacement steroid doses >
             10 mg daily prednisone equivalent are permitted in the absence of active autoimmune
             disease.

          -  Any known active chronic liver disease.

          -  Known history of testing positive for human immunodeficiency virus (HIV) or known
             acquired immunodeficiency syndrome (AIDS).

          -  Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic
             infection.

          -  Known medical condition (for example, a condition associated with diarrhea or acute
             diverticulitis) that, in the investigator's opinion, would increase the risk
             associated with study participation or study drug administration or interfere with the
             interpretation of safety results.

          -  Strong Cytochrome P450 3A4 (CYP3A4) inhibitors
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:the proportion of patients who receive intermittent therapy
Time Frame:Expected duration 5.5 months
Safety Issue:
Description:For cohort I: Assess feasibility of an intermittent dosing schedule, where feasibility is defined in terms of the proportion of patients eligible for intermittent therapy who actually receive it. An underlying acceptance rate of >80% is arbitrarily considered necessary in order to accept the intermittent schedule as feasible whereas an acceptance rate <50% is considered evidence that the intermittent schedule is not feasible

Secondary Outcome Measures

Measure:Change in tumor burden
Time Frame:Expected duration 5.5 months
Safety Issue:
Description:
Measure:Objective Response
Time Frame:Expected duration 5.5 months
Safety Issue:
Description:Number of patients with tumor response per the RECIST 1.1 Criteria: Complete response (CR) is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non target) must have reduction in short axis to <10 mm. Partial response (PR) is defined as a greater than or equal to 30% decrease in the sum of the longest dimensions of the target lesions Progressive disease (PD) is defined as a greater than or equal to 20% increase in the sum of the longest dimensions of the target lesions, or the appearance of one or more new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD
Measure:Length of Progression Free Survival
Time Frame:Expected duration 5.5 months
Safety Issue:
Description:Time from enrollment in the study to progression, when progression is defined as a greater than or equal to 20% increase in the sum of the longest dimensions of the target lesions taking as a reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of one or more new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Measure:Percent of patients who experience grade 3 AE or higher with re-induction ipi/nivo
Time Frame:up to 100 days after end of treatment
Safety Issue:
Description:Estimate toxicity rate in participants undergoing reinduction with ipilimumab/nivolumab as measured by percent of patients who experience grade 3 AE or higher

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Case Comprehensive Cancer Center

Trial Keywords

  • Kidney Cancer
  • Metastatic
  • Nivolumab

Last Updated

December 11, 2019