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    Summary
    EudraCT Number:2014-001286-28
    Sponsor's Protocol Code Number:CA209172
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-08-13
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedDenmark - DHMA
    A.2EudraCT number2014-001286-28
    A.3Full title of the trial
    A Single-Arm, Open-Label, Multicenter Clinical Trial with Nivolumab (BMS-936558) for Subjects with Histologically Confirmed Stage III (unresectable) or Stage IV Melanoma Progressing Post Prior Treatment Containing an Anti-CTLA-4 Monoclonal Antibody
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multicenter clinical study with Nivolumab for subjects with confirmed stage III or stage IV melanoma post treament with an Anti-CTLA-4 antibody.
    A.4.1Sponsor's protocol code numberCA209172
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBristol-Myers Squibb International Corporation
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBristol-Myers Squibb International Corporation
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBristol-Myers Squibb International Corporation
    B.5.2Functional name of contact pointGCT-SU
    B.5.3 Address:
    B.5.3.1Street AddressParc de l'Alliance - Avenue de Finlande, 4
    B.5.3.2Town/ cityBraine-l'Alleud
    B.5.3.3Post code1420
    B.5.3.4CountryBelgium
    B.5.6E-mailclinical.trials@bms.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNivolumab
    D.3.2Product code BMS-936558
    D.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNIVOLUMAB
    D.3.9.1CAS number 946414-94-4
    D.3.9.2Current sponsor codeBMS-936558-01
    D.3.9.3Other descriptive nameBMS936558
    D.3.9.4EV Substance CodeSUB32944
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Histologically Confirmed Stage III (unresectable) or Stage IV Melanoma
    E.1.1.1Medical condition in easily understood language
    Melanoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level PT
    E.1.2Classification code 10025671
    E.1.2Term Malignant melanoma stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level PT
    E.1.2Classification code 10025670
    E.1.2Term Malignant melanoma stage III
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this trial are:
    - To determine the rate and frequency of high-grade (CTCAE v4.0 Grade 3 or higher), treatment-related, select adverse events in subjects with histologically confirmed stage III (unresectable) or stage IV melanoma and progression post prior treatment containing an anti-CTLA-4 monoclonal antibody, treated with nivolumab (BMS-936558) at a dose of 3 mg/kg every two weeks for a maximum of 24 months.
    E.2.2Secondary objectives of the trial
    The secondary objectives:
    - To characterize the outcome (duration of treatment and grade of resolution) of high-grade (CTCAE v4.0 Grade 3 or higher), select adverse events in subjects with histologically confirmed stage III (unresectable) or stage IV melanoma and progression post prior treatment containing an anti-CTLA-4 monoclonal antibody, treated with nivolumab (BMS-936558) at a dose of 3 mg/kg every 2 weeks for a maximum of 24 months.
    - To estimate overall survival (OS) in all treated subjects
    - To estimate Investigator-assessed best overall response (BOR)

    Exploratory objectives: Refer to study protocol
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    a) Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal subject care.
    b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the study.
    2. Target Population
    a) Subjects with histologically confirmed malignant melanoma
    b) Eastern Cooperative Oncology Group (ECOG) Performance Status:
    i) PS 0 to 1 (Cohort 1)
    ii) PS 2 (Cohort 2; maximum of 300; clinical risk benefit ratio of Cohort 2 will be
    monitored by the Scientific Steering Committee and evaluated after treatment of n = 50 for at least 2 months)
    c) Previously treated unresectable stage III or stage IV melanoma as per the American Joint Committee on Cancer 2010 Guidelines 30 regardless of BRAF mutation status
    d) Subjects must have experienced evaluable RECIST 1.1-defined evaluable disease progression
    e) Prior treatment with chemotherapy, interferon (adjuvant setting), IL-2, BRAF/MEK inhibitors for subjects with known BRAF mutations, MEK inhibitors for NRAS mutations, and cKIT inhibitor subjects with known cKIT mutations are allowed
    f) Subjects are eligible if CNS metastases are treated and subjected are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to enrollment. In addition, subjects must be either off corticosteroids or on a stable or decreasing dose of ≤10 mg daily prednisone (or equivalent)
    g) Prior chemotherapy or immunotherapy (tumor vaccine, cytokine, or growth factor given to control the cancer) must have been completed at least 4 weeks before study drug administration, and all adverse events have either returned to baseline or stabilized
    h) Prior palliative radiotherapy must have been completed at least 2 weeks prior to study drug administration
    i) Prior targeted therapy must have been completed at least 2 weeks prior to study drug administration
    j) Prior anti-CTLA-4 therapy must have been completed at least 6 weeks before study drug administration
    k) Prior radiotherapy or radiosurgery must have be completed at least 2 weeks prior to the first dose of study drug
    l) Primary uveal/ocular and mucosal melanoma are allowed
    m) Screening laboratory values must meet the following criteria prior to commencement of treatment:
    i) WBCs ≥ 2000/μL
    ii) Neutrophils ≥1500/μL
    iii) Platelets ≥ 100 x 10³/μL
    iv) Hemoglobin ≥ 9.0 g/dL
    v) Serum creatinine of ≤ 1.5 X ULN or creatinine clearance > 40 mL/minute (using Cockcroft/Gault formula)
    (1) Female CrCl= [(140- age in years) x weight in kg x 0.85) ÷(72 x serum creatinine in mg/ dL)]
    (2) Male CrCl= [(140- age in years) x weight in kg x 1.00) ÷(72 x serum creatinine in mg/ dL)]
    vi) AST ≤ 3 X ULN
    vii)ALT ≤ 3 X ULN
    viii) Total bilirubin ≤ 1.5x ULN (except patients with Gilbert Syndrome who must have total bilirubin < 3.0 mg/dL)
    n) Subject Re-enrollment: This study does not permit the re-enrollment of a subject that has discontinued the study as a pre-treatment failure.

    3. Age and Reproductive Status
    a) Men and women, aged ≥18 years
    b) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
    c) Women must not be breastfeeding
    d) WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug (s) nivolumab plus 5 half-lives of study drug nivolumab (5 times the half-life = 125 days) plus 30 days (duration of ovulatory cycle) for a total of 155 days or 23 weeks post-treatment completion.
    e) Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug nivolumab plus 5 half-lives of the study drug (125 days) plus 90 days (duration of sperm turnover) for a total of 31 weeks post-treatment completion.
    f) Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, WOCBP subjects must still undergo pregnancy testing as described in this section.
    E.4Principal exclusion criteria
    1. Target Disease Exceptions
    a) Leptomeningeal metastases are excluded
    b) Subjects with untreated, active CNS metastases are excluded

    2. Medical History and Concurrent Diseases
    a) Subjects with active, known, or suspected autoimmune disease. Subjects with Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
    b) Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active
    autoimmune disease.
    c) Subjects with previous malignancies (except non-melanoma skin cancers, in situ bladder cancer, gastric or colon cancers, cervical cancers/dysplasia or breast carcinoma in situ) are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period
    d) Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the subject to receive protocol therapy
    e) Any treatment in a nivolumab trial or treatment in an ipilimumab trial
    f) Known drug or alcohol abuse
    3. Physical and Laboratory Test Findings
    a) Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
    b) Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
    4. Allergies and Adverse Drug Reaction
    a) History of severe hypersensitivity reactions to other monoclonal antibodies
    b) History of allergy or intolerance (unacceptable adverse event) to study drug components or Polysorbate-80-containing infusions.
    c) Subjects with a known history of the following anti-CTLA-4 therapy related adverse reactions based on the CTCAE v4.0 criteria:
    i. Grade ≥ 3 anti-CTLA-4 therapy-related adverse reaction except resolved nausea, fatigue, or endocrinopathies where clinical symptoms were able to be controlled with appropriate hormone replacement therapy
    ii. Any ≥ Grade 2 eye pain or reduction of visual acuity that did not respond to
    topical therapy and did not improve to ≤ Grade 1 severity within 2 weeks of
    starting topical therapy or required systemic treatment
    iii. Any ≥ Grade 3 sensory neurologic toxicity
    iv. Any Grade 4 laboratory abnormalities, except AST, ALT, or T. bilirubin:
    a) AST or ALT > 10 x ULN
    b) T. bilirubin > 5 x ULN
    v. Subjects who required infliximab or other immune suppressants including
    mycophenolic acid for management of drug-related toxicities
    vi. Any other anti-CTLA-4 therapy-related adverse event requiring permanent
    discontinuation of anti-CTLA-4
    vii. History of Grade ≥ 3 neurologic toxicity
    viii. History of Grade ≥ allergy to study drug components
    5. Sex and Reproductive Status
    a) WOCBP who are pregnant or breastfeeding
    b) Women with a positive pregnancy test at enrollment or prior to administration of study medication
    6. Prohibited Treatments and/or Restricted Therapies
    a) The following are prohibited during the study (unless used to treat a drug-related adverse event):
    i) Immunosuppressive agents
    ii) Immunosuppressive doses of systemic corticosteroids (except as stated in the Protocol in Section 3.4.3 or to treat a drug-related adverse event)
    b) Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, non-palliative radiation therapy, or standard or investigational agents for treatment of melanoma)
    c) Subjects who received prior therapy with an anti-PD-1, anti-PD-L1 or anti-PD-L2, (or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways except for anti-CTLA-4 therapy as described above)
    d) Prior radiotherapy must have been completed at least 14 days prior to start of study treatment. See Protocol Section 3.4.2 for guidance on concomitant palliative radiotherapy.
    e) Subjects may continue to receive hormone replacement therapy if initiated prior to first dose of study therapy

    7. Other Exclusion Criteria
    a) Prisoners or subjects who are involuntarily incarcerated
    b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoints include:
    - Rate and frequency for high-grade (CTCAE v4.0 Grade 3 or higher) treatment-related, select adverse events
    - Rate and frequency of AEs regardless of causality
    - Rate and frequency of treatment-related AEs
    - Rate and frequency of any AEs of special interest (AEOSI), such as pulmonary, gastrointestinal, cutaneous, renal, hepatic, pancreatic, endocrine, infusion related, or hypersensitivity
    E.5.1.1Timepoint(s) of evaluation of this end point
    up to 24 months
    E.5.2Secondary end point(s)
    The secondary endpoints include:
    - Outcome (grade of resolution; duration of AE-specific treatment) of all high-grade (CTCAE v4.0 Grade 3 or higher) treatment-related adverse events
    - Time to OS and survival at Years 1 and 2 after treatment and beyond.
    - Investigator-assessed BOR

    The exploratory endpoints include:
    - Safety, tolerability, OS, and Investigator-assessed BOR in subjects with BRAF-mutated melanoma
    - Safety, tolerability, OS, and Investigator-assessed BOR in subjects with inactive brain metastasis
    - Safety, tolerability, OS, and Investigator-assessed BOR in subjects with Performance Status (0-1 or 2)
    - Safety, tolerability, OS, and Investigator-assessed BOR in patients with uveal/ocular and mucosal melanoma
    - Quality of Life as mean and change from baseline in domain scores and health status index based on EORTC-QLQ-C30 and EQ-5D of the full safety analysis set
    E.5.2.1Timepoint(s) of evaluation of this end point
    up to 24 months
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA210
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    Belgium
    Bulgaria
    Croatia
    Czech Republic
    Denmark
    Estonia
    Finland
    Germany
    Greece
    Hungary
    Iceland
    Ireland
    Italy
    Latvia
    Lithuania
    Malta
    Netherlands
    Norway
    Poland
    Portugal
    Romania
    Russian Federation
    Slovakia
    Slovenia
    Spain
    Sweden
    Switzerland
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 1080
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 720
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1675
    F.4.2.2In the whole clinical trial 1800
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Normal standard of care.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-09-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-12-01
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-01-18
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