Clinical Trials /

TNF-Inhibitor as Immune Checkpoint Inhibitor for Advanced MELanoma

NCT03293784

Description:

This is a Phase 1b, open-label study of immune checkpoints inhibitors Nivolumab+Ipilimumab administered in combination with the anti-TNF-α either Infliximab or Certolizumab, in patients with advanced melanoma.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: TNF-Inhibitor as Immune Checkpoint Inhibitor for Advanced MELanoma
  • Official Title: TNF-Inhibitor as Immune Checkpoint Inhibitor for Advanced MELanoma - A Phase Ib Clinical Study

Clinical Trial IDs

  • ORG STUDY ID: 16CUTA07
  • NCT ID: NCT03293784

Conditions

  • Melanoma

Purpose

This is a Phase 1b, open-label study of immune checkpoints inhibitors Nivolumab+Ipilimumab administered in combination with the anti-TNF-α either Infliximab or Certolizumab, in patients with advanced melanoma.

Detailed Description

      The study will be conducted in 2 consecutive parts:

        -  Part 1 with 2 parallel cohorts (Nivolumab+Ipilimumab administered in combination with
           anti-TNF-α Certolizumab (Cohort 1) and Nivolumab+Ipilimumab administered in combination
           with anti-TNF-α Infliximab (Cohort 2)). 6 patients will be included in each cohort.

        -  Part 2 (expansion phase) will then be scheduled after the most promising combination has
           been confirmed; the choice of the combination will be based on safety, efficacy, and PD
           data observed in both cohorts during the Part 1 of the study.
    

Trial Arms

NameTypeDescriptionInterventions
COHORT 1OtherNivolumab+Ipilimumab in combination with Anti TNF-α Certolizumab
    COHORT 2OtherNivolumab+Ipilimumab in combination with Anti TNF-α Infliximab

      Eligibility Criteria

              Inclusion Criteria:
      
                1. Patient with histologically-proven metastatic and/or unresectable melanoma (stage
                   IIIc-IV, M1a-c as per AJCC 2009), including mucosal melanoma, without evidence of
                   active intra-cranial disease.
      
                2. Subjects are included regardless of BRAFV600 mutation status. BRAFV600 mutation status
                   must be documented.
      
                3. Measurable disease per RECIST 1.1
      
                4. Age ≥18 years and ≤70 years at the time of study entry.
      
                5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
      
                6. Life expectancy of at least 3 months.
      
                7. Patient able to participate and willing to give informed consent prior to performance
                   of any study-related procedures and to comply with the study protocol.
      
                8. Screening laboratory values must meet the following criteria and should be obtained
                   prior to commencement of treatment:
      
                   White blood count (WBC) ≥ 2000/μL Neutrophils ≥ 1500/μL Platelets ≥ 100 x103/μL
                   Hemoglobin > 9.0 g/dL
      
                   Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the
                   Cockcroft-Gault formula below):
      
                   Female CrCl = (140 - age in years) x weight in kg x 0.85 / 72 x serum creatinine in
                   mg/dL Male CrCl = (140 - age in years) x weight in kg x 1.00 / 72 x serum creatinine
                   in mg/dL AST/ALT ≤ 3 x ULN (except subjects with hepatic metastasis, who can have
                   AST/ALT ≤ 5 x ULN) Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome,
                   who can have total bilirubin < 3.0 mg/dL)
      
                9. Adequate cardiac and respiratory functions defined as New York Heart Association
                   (NYHA) class 1 and SaO2 > 90%.
      
               10. Patient must be naïve to systemic treatment for locally advanced and/or metastatic
                   disease (i.e., no prior systemic anticancer therapy for advanced disease; stage IIIc
                   and IV). Prior adjuvant therapies (including Interferon α and Ipilimumab) is permitted
                   if it was completed at least 12 weeks before start of treatment and all related AEs
                   have either returned to baseline or stabilized.
      
               11. Prior radiotherapy or radiosurgery must have been completed at least 4 weeks prior to
                   the first dose of the study treatment.
      
               12. Women of childbearing potential (WOCBP) must use two appropriate methods of
                   contraception to avoid pregnancy for 23 weeks (30 days plus the time required for
                   Nivolumab/Ipilimumab to undergo five half-lives) after the last dose of
                   investigational drug.
      
               13. Women of childbearing potential must have a negative serum or urine pregnancy test
                   (minimum sensitivity 25IU/L or equivalent units of HCG) within 24 hours prior to the
                   start of study treatment.
      
               14. Men who are sexually active with WOCBP must use two contraceptive methods including at
                   least one method with a failure rate of less than 1% per year for a period of 31 weeks
                   after the last dose of investigational product. Women who are not of childbearing
                   potential (i.e., who are postmenopausal or surgically sterile) as well as azoospermic
                   men do not require contraception.
      
               15. Absence of any psychological, familial, sociological or geographical condition that
                   potentially hampers compliance with the study protocol and follow-up after treatment
                   discontinuation schedule.
      
               16. Patient affiliated to a Social Health Insurance in France.
      
               17. Patient must provide written informed consent prior to any study specific procedures.
      
              Exclusion Criteria:
      
                1. Patient pregnant, or breast-feeding.
      
                2. Uveal melanoma.
      
                3. Active and/or symptomatic intra cranial metastasis (including melanomatous
                   meningitis). Patients with intra cranial metastasis may be eligible if all known
                   lesions have been treated with stereotactic radiotherapy or surgery or both AND there
                   has been no magnetic resonance imaging (MRI) evidence of disease progression in the
                   CNS for ≥ 4 weeks after treatment and within 28 days prior the first dose of study
                   drug administration.
      
                4. Previous treatment with B-RAF or MEK inhibitors within 12 weeks prior start of
                   treatment.
      
                5. Hypersensitivity to the drugs of the study.
      
                6. Any 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.
      
                7. Clinically significant cardiac dysfunction including congenital, familial, and genetic
                   cardiac disorders, current instable angina, current symptomatic congestive heart
                   failure of NYHA class 2 and higher, current uncontrolled hypertension ≥ grade 3; Left
                   Ventricular Ejection Fraction (LVEF) below institutional lower limit of normal (LLN)
                   or below 50%, whichever is lower.
      
                8. Patient with active malignancy other than melanoma or a history of previous within the
                   past 3 years; except for patients with resected Basal cell carcinoma or resected
                   Spindle cell carcinoma, resected carcinoma in situ of the cervix and resected
                   carcinoma in situ of the breast.
      
                9. History of untreated tuberculosis and/or positive quantiferon test without previous
                   prophylaxis tuberculosis treatment, or untreated active infection with mycobacterium
                   tuberculosis. For patients with asymptomatic (including radiologic symptoms) infection
                   with mycobacterium tuberculosis, inclusion may be possible after 4 weeks of adequate
                   antibiotics treatment.
      
               10. Active, known or suspected autoimmune disease including but not restricted to multiple
                   sclerosis, optical nevritis and demyelinating neuropathy. 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.
      
               11. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus
                   (HCV ribonucleic acid or HCV antibody) indicating acute or chronic infection.
      
               12. Known history of testing positive for human immunodeficiency virus (HIV) or known
                   acquired immunodeficiency syndrome (AIDS).
      
               13. Vaccination with any live attenuated conventional vaccine within the 3 months
                   preceding the start of study treatment.
      
               14. Any current severe or uncontrolled disease, including, but not limited to ongoing or
                   active infection.
      
               15. Patient included in another study with an experimental molecule and/or procedure.
      
               16. Unwillingness or inability to provide written informed consent.
      
               17. Any psychological, familial, geographic or social situation, according to the judgment
                   of investigator, potentially preventing the compliance of treatment and the study
                   protocol.
      
               18. Patient who has forfeited his/her freedom by administrative or legal award or who is
                   under guardianship.
            
      Maximum Eligible Age:70 Years
      Minimum Eligible Age:18 Years
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Dose Limiting Toxicities (DLT) incidence.
      Time Frame:12 weeks per patient
      Safety Issue:
      Description:For each patient, DLT incidence will be evaluated during the Part 1 of the study: 12 weeks after the initial dose of study drug.

      Secondary Outcome Measures

      Measure:Safety and tolerability according to the classification of the National Cancer Institute Common Toxicity Criteria for Adverse Effects (NCI-CTCAE) Version 4.03.
      Time Frame:15 months per patient
      Safety Issue:
      Description:The assessment of safety and tolerability will be based on the incidence of Adverse Events (AEs), Serious Adverse Events, AEs leading to discontinuation, and death. In addition, clinical laboratory test abnormalities will be examined. Tolerability will be evaluated by collecting dose interruptions and dose delays.
      Measure:Progression Free Survival
      Time Frame:24 months per patient
      Safety Issue:
      Description:Progression Free Survival (PFS) is defined as the time from inclusion until progression or deaths; patients alive at last follow-up news are censored at this date.
      Measure:Objective Response Rate
      Time Frame:24 months per patient
      Safety Issue:
      Description:Objective Response Rate (ORR) is defined as the number of patients with Best Overall Response divided by the number of included patients in each cohort.

      Details

      Phase:Phase 1
      Primary Purpose:Interventional
      Overall Status:Recruiting
      Lead Sponsor:Institut Claudius Regaud

      Trial Keywords

      • Melanoma
      • Immune checkpoint
      • Nivolumab
      • Ipilimumab
      • Infliximab
      • Certolizumab
      • PD-1
      • TNFa
      • CTLA-4

      Last Updated

      June 10, 2020