Clinical Trials /

A BIOmarker Driven Trial With Nivolumab and Ipilimumab or VEGFR tKi in Naïve Metastatic Kidney Cancer

NCT02960906

Description:

Disease and Stage: naïve metastatic kidney cancer. A multicenter, randomized, a Phase 2 BIOmarker driven trial with Nivolumab and Ipilimumab or VEGFR tKi in naïve metastatic Kidney cancer

Related Conditions:
  • Clear Cell Renal Cell Carcinoma
Recruiting Status:

Unknown status

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A BIOmarker Driven Trial With Nivolumab and Ipilimumab or VEGFR tKi in Naïve Metastatic Kidney Cancer
  • Official Title: A Phase 2 BIOmarker Driven Trial With Nivolumab and Ipilimumab or VEGFR tKi in Naïve Metastatic Kidney Cancer

Clinical Trial IDs

  • ORG STUDY ID: BIONIKK
  • NCT ID: NCT02960906

Conditions

  • Clear Cell Metastatic Renal Cell Carcinoma

Interventions

DrugSynonymsArms
NivolumabBMS-936558, OpdivoccRCC molecular subgroup 1: 1A
IpilimumabYERVOY, BMS-734016ccRCC molecular subgroup 1: 1B
PazopanibVotrientccRCC molecular subgroup 2: 2C
SunitinibSutentccRCC molecular subgroup 2: 2C

Purpose

Disease and Stage: naïve metastatic kidney cancer. A multicenter, randomized, a Phase 2 BIOmarker driven trial with Nivolumab and Ipilimumab or VEGFR tKi in naïve metastatic Kidney cancer

Detailed Description

      Research Hypothesis: Molecular groups of ccrcc will define patients who will respond to
      nivolumab alone, nivolumab combined with ipilimumab, or VEGFR-TKI (sunitinib or pazopanib) in
      subjects with previously untreated metastatic renal cell carcinoma (mRCC).

      Conditions:

        -  Advanced or metastatic RCC: previously untreated in metastatic setting.

        -  Frozen tumor samples available for molecular group determination.

        -  Determination of molecular subgroup prior to randomization.

      Product(s):

        -  Nivolumab administered IV over 60 minutes at 3 mg/kg combined with ipilimumab
           administered IV over 30 minutes at 1 mg/kg every 3 weeks for 4 doses followed by
           nivolumab administered IV over 60 minutes at 3 mg/kg every 2 weeks or nivolumab a l o n
           e administered IV over 60 minutes at 3 mg/kg every 2 weeks (molecular group 1 and 4), or
           TKI (molecular group 2 and 3), pazopanib or sunitinib according to investigator's choice
           until disease progression, unacceptable toxicity or other reasons specified in the
           protocol.

      Biological assessments:

      Molecular groups (1 to 4) will be determined for all patients from frozen tumor tissue
      samples or from fresh tumor samples immediately stored in "RNA later" medium.

      Further exploratory biological assessments will be performed in order to define predictive
      biomarkers of response to N+I, N alone or TKI (sunitinib or pazopanib) by analyzing tumor
      specimens and blood samples:

        -  To assess gene expression of immune population markers in the primary tumor as well as
           in the metastases before beginning treatment, and at progression if safely achievable.

        -  Gene expression analysis will be performed from frozen and FFPE tumor tissue in order to
           compare the two methods.

        -  To assess the density and phenotype of selected immune populations (CD8, CD3/CD20, PD-1,
           TIM-3, LAG3, FoxP3) as well as the phenotype of tumor cells (PD-L1, PD-L2) by
           immunohistochemistry (IHC) in the primary tumor and metastases, before treatment
           initiation and at progression if safely achievable.

        -  To assess the functional status of peripheral blood lymphocytes (PBL) by flow cytometry,
           before treatment initiation, during treatment, and at progression.

        -  To quantify plasmatic angiogenesis-related (i.e. VEGF-A, VEGF-C its soluble receptors
           VEGFR-1 and 2 and co-receptors neuropilin 1 and 2, angiopoietins, SDF-1, PDGFs…)) and
           endothelial cell-derived molecules (i.e. endoglin, VE-cadherin) before treatment
           initiation, during treatment, and at progression.

        -  To correlate plasmatic angiogenesis-related molecules with tumor vascularization studied
           by immunofluorescence (IF) and a multi-spectral analyzer (Vectra technology) on tumor
           tissue.

        -  To investigate a predictive role of the response of CXCL7 and sCD146 to TKI, nivolumab
           and/or nivolumab+ipilimumab.

      Statistical Considerations:

      An adaptative design will be used to ensure that conclusions can be made with a limited
      number of patients in each molecular group, which is the major constraint of the study.

      Sample Size: Approximately 150 patients are planned to be treated. Given an expected failure
      rate of molecular grouping of less than 20%, 180 patients must be included.
    

Trial Arms

NameTypeDescriptionInterventions
ccRCC molecular subgroup 1: 1AExperimentalccRCC molecular subgroup 1 -> randomisation: subjects with ccRCC1 treated with nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.
  • Nivolumab
ccRCC molecular subgroup 1: 1BExperimentalccRCC molecular subgroup 1 -> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.
  • Nivolumab
  • Ipilimumab
ccRCC molecular subgroup 4: 4AExperimentalccRCC molecular subgroup 4 -> randomisation: subjects with ccRCC1 treated with nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.
  • Nivolumab
ccRCC molecular subgroup 4: 4BExperimentalccRCC molecular subgroup 4 -> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.
  • Nivolumab
  • Ipilimumab
ccRCC molecular subgroup 2: 2CExperimentalccRCC molecular subgroup 2 -> randomisation: TKI (sunitinib 50mg daily or Pazopanib 800mg daily) according to investigator's choice until disease progression, unacceptable toxicity or other reasons specified in the protocol.
  • Pazopanib
  • Sunitinib
ccRCC molecular subgroup 2: 2BExperimentalccRCC molecular subgroup 2 -> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.
  • Nivolumab
  • Ipilimumab
ccRCC molecular subgroup 3: 3BExperimentalccRCC molecular subgroup 3 -> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.
  • Nivolumab
  • Ipilimumab
ccRCC molecular subgroup 3: 3CExperimentalccRCC molecular subgroup 3 -> randomisation: TKI (sunitinib 50mg daily or Pazopanib 800mg daily) according to investigator's choice until disease progression, unacceptable toxicity or other reasons specified in the protocol.
  • Pazopanib
  • Sunitinib

Eligibility Criteria

        Key Inclusion Criteria:

          -  Histological confirmation of RCC with a clear-cell component. Patients with TFE3 or
             TFEB translocation proven by cytogenetic analysis or by fluorescence in situ
             hybridization (FISH) are eligible.

          -  Metastatic (American Joint Committee on Cancer [AJCC] Stage IV) RCC

          -  No prior systemic therapy for mRCC

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2

          -  Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

          -  Frozen tumor samples (primary tumor and/or metastasis biopsies) must be available and
             received by the central laboratory (Cordelier Research Center) to determine molecular
             groups. (Note: fine needle aspiration [FNA] and bone metastases samples are not
             acceptable for submission).

          -  Molecular group has to be determined prior to randomization.

          -  Formalin-fixed, paraffin-embedded (FFPE) tumor tissue available for biomarker (gene
             expression and immunohistochemistry (IHC)) analysis.

        Key Exclusion Criteria:

          -  Any untreated CNS metastases. Patients with CNS metastases will be eligible if they
             are: asymptomatic, without significant oedema, not on corticosteroids, not eligible
             for radiation therapy/surgery or have already received radiation therapy.

          -  Prior systemic treatment with vascular endothelial growth factor (VEGF) or VEGF
             receptor-targeted therapy (including, but not limited to, sunitinib, pazopanib,
             axitinib, tivozanib, and bevacizumab) except in an adjuvant setting with a free
             interval of more than 1 year.

          -  Prior treatment with an anti-programmed cell death protein 1 (PD-1), anti-programmed
             death-ligand 1 (PD-L1), anti-PD-L2, anti-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.

          -  Any active or recent history of a known or suspected autoimmune disease or recent
             history of a syndrome that required systemic corticosteroids (>10 mg daily prednisone
             equivalent) or immunosuppressive medications except for syndromes which would not be
             expected to recur in the absence of an external trigger. Subjects with vitiligo or
             type 1 diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only
             requiring hormone replacement are permitted to enroll.

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

          -  Uncontrolled adrenal insufficiency.

          -  Ongoing symptomatic cardiac dysrhythmias, uncontrolled atrial fibrillation, or
             prolongation of the Fridericia corrected QT (QTcF) interval defined as >450 msec for
             males and >470 msec for females, where QTcF = QT / 3√RR.

          -  Poorly controlled hypertension (defined as systolic blood pressure (SBP) of >150 mmHg
             or diastolic blood pressure (DBP) of >90 mmHg), despite antihypertensive therapy.

          -  History of any of the following cardiovascular conditions within 12 months of
             enrollment: cardiac angioplasty or stenting, myocardial infarction, unstable angina,
             coronary artery by-pass graft surgery, symptomatic peripheral vascular disease, class
             III or IV congestive heart failure, as defined by the New York Heart Association.

          -  History of cerebrovascular accident including transient ischemic attack within the
             past 12 months.

          -  History of deep vein thrombosis (DVT) unless adequately treated with low molecular
             weight heparin.

          -  History of pulmonary embolism within the past 6 months unless stable, asymptomatic,
             and treated with low molecular weight heparin for at least 6 weeks.

          -  Known history of COPD (of any stage).

          -  Known history of uveitis or complaint of double vision.

          -  History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
             within the past 6 months.

          -  Serious, non-healing wound or ulcer.

          -  Evidence of active bleeding or bleeding susceptibility; or medically significant
             hemorrhage within prior 30 days.

          -  Any requirement for anti-coagulation, except for low molecular weight heparin.

          -  Prior malignancy active within the previous 3 years except for locally curable cancers
             that have been apparently cured, such as basal or squamous cell skin cancer,
             superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.

          -  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 (e.g., 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.

          -  Known history of hyperesthesia, hypoesthesia, paresthesia, dysesthesia, peripheral
             motor neuropathy, peripheral sensory, neuropathy, and polyneuropathy.

          -  Major surgery (e.g., nephrectomy) less than 35 days prior to the first dose of study
             drug.

          -  Focal radiation therapy less than 14 days prior to the first dose of study drug.

          -  Receiving concomitant CYP3A4 inducers or strong CYP3A4 inhibitors

          -  Impairment of gastrointestinal function or gastrointestinal disease that may
             significantly alter the absorption of cabozantinib (e.g., malabsorptive disorder,
             ulcerative disease, uncontrolled nausea, vomiting, diarrhea, or small bowel
             resection).

          -  Any of the following laboratory test findings:

               1. WBC <2,000/mm3

               2. Hemoglobin ≤9.0 g/dL

               3. Neutrophils <1,500/mm3

               4. Platelets <100,000/mm3

               5. AST or ALT >3 x ULN (>5 x ULN if liver metastases are present)

               6. Lipase and amylase > 1.5 ULN

               7. Total Bilirubin >1.5 x ULN (except subjects with Gilbert Syndrome, who can have
                  total bilirubin <3.0 mg/dL)

               8. Serum creatinine >1.5 x ULN or creatinine clearance <40 mL/min (measured or
                  calculated by Cockroft-Gault formula)

               9. Proteinuria: patients with ≥2+ protein on urine dipstick at baseline must undergo
                  a 24-hour urine collection for protein then if > 1.0 g of protein patient will
                  not be included.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:ORR evaluation according to molecular groups (ccRCC1 to 4) and assigned treatment
Time Frame:36 months
Safety Issue:
Description:ORR evaluation according to molecular groups (ccRCC1 to 4) and assigned treatment (nivolumab monotherapy, nivolumab combined with ipilimumab, or TKI: sunitinib or pazopanib), based on Investigator assessments.

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:36 months
Safety Issue:
Description:progression-free survival (PFS) in subjects with previously untreated mRCC according to molecular groups and assigned treatment, based on Investigator radiological assessments.
Measure:Overall Survival
Time Frame:36 months
Safety Issue:
Description:To evaluate OS in subjects with previously untreated mRCC according to molecular groups and assigned treatment.
Measure:Objective response rate at 22 weeks
Time Frame:at 22 weeks
Safety Issue:
Description:To evaluate objective response rate at 22 weeks as a surrogate of other endpoints according to molecular groups and assigned treatment.
Measure:Duration of treatment (DOT)
Time Frame:36 months
Safety Issue:
Description:To evaluate the duration of treatment (DOT) of nivolumab combined with ipilimumab or nivolumab alone or cabozantinib in subjects with previously untreated mRCC according to their molecular subgroup (1&4 vs 2&3).
Measure:Duration of response (DOR)
Time Frame:36 months
Safety Issue:
Description:To evaluate the duration of response (DOR) of nivolumab combined with ipilimumab or nivolumab alone or cabozantinib in subjects with previously untreated mRCC according to their molecular subgroup (1&4 vs 2&3).
Measure:Number of Participants With Treatment-Related Adverse Events
Time Frame:36 months
Safety Issue:
Description:To estimate the incidence of AEs associated with nivolumab combined with ipilimumab or nivolumab alone or cabozantinib in all treated subjects with previously untreated mRCC.
Measure:Gene expression of immune population markers
Time Frame:at baseline at progression (36 months maximum)
Safety Issue:
Description:To assess gene expression of immune population markers in the primary tumor as well as in the metastases before beginning treatment, and at progression if safely achievable.populations (CD3, CD8...) and regulatory markers (PD-1, LAG-3…) within the primary tumor, and metastases whenever possible, using frozen and FFPE tumor tissue.
Measure:Gene expression levels obtained from FFPE
Time Frame:at the end of the study (36 months)
Safety Issue:
Description:Gene expression levels obtained from FFPE tumor tissue (exploratory method) will be compared to those obtained with frozen tumor tissue (standard method).
Measure:Functional status of peripheral blood lymphocytes (PBL)
Time Frame:at baseline, at cycle 2 and at progression (36 months maximum)
Safety Issue:
Description:To assess the functional status of peripheral blood lymphocytes (PBL) by flow cytometry, before treatment initiation, during treatment, and at progression.
Measure:Association between non-immune tissue and circulating biomarkers and outcomes
Time Frame:36 months maximum
Safety Issue:
Description:To explore the association between non-immune tissue and circulating biomarkers and outcomes (ORR, ORR at 22 weeks, OS and PFS).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie

Last Updated

May 28, 2018