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    Summary
    EudraCT Number:2015-001274-17
    Sponsor's Protocol Code Number:CA209-401
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-09-08
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2015-001274-17
    A.3Full title of the trial
    Clinical Trial of Nivolumab (BMS-936558) Combined with Ipilimumab Followed by Nivolumab Monotherapy as First-Line Therapy of Subjects with Histologically Confirmed Stage III (Unresectable) or Stage IV Melanoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to assess the efficacy and safety of Nivolumab and Ipilimumab in the treatment of patients with Stage III or IV Melanoma. Patients will then receive Nivolumab until the end of the study.
    A.3.2Name or abbreviated title of the trial where available
    CheckMate 401: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 401
    A.4.1Sponsor's protocol code numberCA209-401
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1168-2955
    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
    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.IMP: 2
    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 nameIpilimumab
    D.3.2Product code BMS-734016
    D.3.4Pharmaceutical form Concentrate for solution for 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 INNIPILIMUMAB
    D.3.9.1CAS number 477202-00-9
    D.3.9.2Current sponsor codeBMS-734016
    D.3.9.3Other descriptive nameBMS734016
    D.3.9.4EV Substance CodeSUB22577
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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
    Stage III (Unresectable) or Stage IV Melanoma
    E.1.1.1Medical condition in easily understood language
    Skin Cancer
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    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 20.0
    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 study is to determine the incidence of high-grade (CTCAE v4.0 Grades 3-5), treatment-related, select adverse events of potentially immune-mediated etiology (pulmonary, gastrointestinal, skin, renal, hepatic, endocrine, infusion-related, or hypersensitivity) of nivolumab plus ipilimumab combination regimen as firstline therapy for unresectable or metastatic melanoma.

    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are:
    *To determine the incidence and to characterize the outcome (duration of serious adverse events [SAE] treatment, dose of immune-modulating agents [ie, steroids] used, time to event onset, and event resolution, and worst grade of event) of high-grade (CTCAE v4.0 Grade 3 or higher), select adverse events of potentially immune-mediated etiology in subjects with unresectable or metastatic melanoma treated with nivolumab and ipilimumab combination regimen
    *To estimate overall survival (OS) in all treated subjects
    *To assess safety, tolerability, investigator-assessed objective response rate (ORR), progression-free survival (PFS), and OS in all subjects and in a subset of with Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1, ECOG PS 2, ocular and mucosal melanoma, and brain metastasis
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    a)Subjects with histologically-confirmed unresectable stage III or stage IV melanoma as per AJCC 2010
    staging system, including mucosal and ocular melanoma, regardless of BRAF mutation status
    b)Subjects are included if they are newly diagnosed with advanced/metastatic disease and have not receivedprior systemic treatment for their advanced disease.
    NOTE: Prior adjuvant or neoadjuvant melanoma therapy (including anti-CTLA-4, anti-PD-1, anti-PD-L1,anti-PD-L2, or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways, such as anti-CD-137) is permitted if the therapy was used in the adjuvant or neoadjuvant setting but not in the metastatic setting. These drugs must be discontinued 6 months prior to study entry. All AEs related to prior adjuvant or neoadjuvant therapy must have either returned to baseline, and eligible patients
    must not have experienced severe or life-threatening irAEs except those that are unlikely to reoccur with standard countermeasures (eg, hormone replacement after adrenal crisis).
    c)Subjects with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 2 weeks after treatment is complete and within 6 weeks prior to first dose of study drug administration. (If MRI is contraindicated, CT scan is acceptable). There must also be no requirement for high doses of systemic corticosteroids that could result in immunosuppression (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
    i)Subjects are eligible if they have previously untreated brain metastases and are neurologically asymptomatic (This criterion is restricted to the investigators who have treated at least 3 patients with nivolumab plus ipilimumab combination regimen):
    (1)No clinical requirement for local intervention (surgery, radiosurgery, corticosteroid therapy) or other systemic therapy.
    (2)Subjects must be free of neurologic signs and symptoms related to metastatic brain lesions and must not have received systemic corticosteroid therapy in the 14 days prior to beginning protocol therapy.
    ii)If patients had been previously treated and then developed asymptomatic progression (This criterion with details below is restricted to the investigators who have treated at least 3 patients with nivolumab plus ipilimumab combination regimen)
    (1)Prior stereotactic radiotherapy (SRT) and prior excision of up to 3 melanoma brain metastases is permitted if there has been complete recovery, with no neurologic sequelae.
    (2)Growth or change in a lesion previously irradiated will not be considered measurable. Regrowth in cavity of previously excised lesion will not be considered measurable.
    (3)Any prior surgery or radiotherapy must have occurred at least 6 weeks before the start of dosing for this study.
    d)ECOG PS 0-1
    e)ECOG PS of 2 (This criterion is restricted to investigators who have treated at least 3 patients with nivolumab plus ipilimumab combination regimen)
    f)Tissue tumor (archival or recent acquisition) must be available (block or a minimum of 10 unstained slides of FFPE tissue) for correlative studies
    E.4Principal exclusion criteria
    a)Leptomenigeal metastases
    b)As of Amendment 04, this criterion is no longer applicable
    c)Subjects previously treated with SRT > 3 lesions in the brain
    d)Brain lesion > 3 cm
    e)History of carcinomatous meningitis (lumbar puncture is not required)
    f)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.
    g)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.
    h)All toxicities attributed to prior anti-cancer therapy other than alopecia, fatigue, or peripheral neuropathy must have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration of study drug.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the incidence of high-grade (CTCAE v4.0 Grade 3-5), treatment-related, select adverse events of potentially immune-mediated etiology (pulmonary, gastrointestinal, skin, renal, hepatic, endocrine, infusion-related, or hypersensitivity).
    E.5.1.1Timepoint(s) of evaluation of this end point
    The initial tumour assessment is completed at week 12 (+/- 5 days) after the first treatment dose
    E.5.2Secondary end point(s)
    * Incidence of all high-grade (Grades 3-5), select adverse events
    * Median time to onset and median time to resolution (Grades 3-4) of select adverse events
    * Resolution of an AE is a subject experiencing complete resolution or improvement to the baseline grade for the AE
    * OS is defined as the time from first dosing date to the date of death. A subject who has not died will be censored at last known date alive.
    * Safety and tolerability will be measured by the incidence of all AEs, treatment-related AEs, serious AEs, deaths, laboratory abnormalities, and select AEs such as pulmonary, gastrointestinal, skin, renal, hepatic, endocrine, infusion-related, or hypersensitivity.
    * The ORR is defined as the number of subjects with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of all treated subjects. BOR is defined as the best response designation, recorded between the date of first dose and the date of the initial objectively documented tumor progression by the investigator per RECIST v1.1 or the date of subsequent therapy, whichever occurs first.
    For subjects without documented progression or subsequent therapy, all available response designations will contribute to the BOR determination.
    * Investigator-assessed PFS is defined as radiological evidence of progression, significant clinical symptomatic progression, or the need to introduce a non-study drug therapy.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Nivolumab plus Ipilimumab: Adverse Event assessments are done during office visits and by weekly calls to subject during weeks the subject is not in the office for a clinic visit.

    Nivolumab monotherapy: Every 2 weeks (+/- 3 days)
    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 No
    E.6.5Efficacy No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA104
    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
    Australia
    Austria
    Belgium
    Finland
    France
    Germany
    Ireland
    Italy
    Norway
    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 years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    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: 308
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 307
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state95
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 515
    F.4.2.2In the whole clinical trial 615
    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)
    Subjects who continue to demonstrate clinical benefit at the conclusion of the study will be eligible to receive BMS supplied study drug, for the maximum treatment duration specified in Section 3.1 of the Protocol. Study drug will be provided via an extension of the study, a rollover study requiring approval by responsible health authority and ethics committee or through another mechanism at the discretion of BMS.
    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 Decision2016-10-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-11-28
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-02-10
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