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    Summary
    EudraCT Number:2014-002605-38
    Sponsor's Protocol Code Number:CA224-020
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-15
    Trial 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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2014-002605-38
    A.3Full title of the trial
    A Phase 1/2a Dose Escalation and Cohort Expansion Study of the Safety,Tolerability, and Efficacy of Anti-LAG-3 Monoclonal Antibody (BMS-986016) Administered Alone and in Combination with Anti-PD-1 Monoclonal Antibody (Nivolumab, BMS-936558) in Advanced Solid Tumors
    Studio di Fase 1/2a di incremento della dose e espansione della coorte per valutare la sicurezza, la tollerabilit¿ e l¿efficacia dell¿anticorpo monoclonale anti-LAG-3 (BMS-986016) somministrato in monoterapia e in combinazione con l¿anticorpo monoclonale anti-PD-1 (Nivolumab, BMS-936558) nei tumori solidi in stadio avanzato.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety Study of Anti-LAG-3 With and Without Anti-PD-1 in the Treatment of Solid Tumors
    Studio per valutare la sicurezza, la tollerabilit¿ e l¿efficacia dell¿anticorpo monoclonale anti-LAG-3 in monoterapia e in combinazione con Nivolumab, nei tumori solidi in stadio avanzato.
    A.3.2Name or abbreviated title of the trial where available
    CA224-020
    CA224-020
    A.4.1Sponsor's protocol code numberCA224-020
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01968109
    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.5.4Telephone number00000000
    B.5.5Fax number00000000
    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 nameAnti-LAG-3
    D.3.2Product code BMS-986016
    D.3.4Pharmaceutical form 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 INNrelatlimab
    D.3.9.2Current sponsor codeBMS-986016
    D.3.9.3Other descriptive nameanti-LAG-3
    D.3.9.4EV Substance CodeSUB168199
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 nameNivolumab
    D.3.2Product code BMS-936558
    D.3.4Pharmaceutical form 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 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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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: 3
    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 nameAnti-LAG-3
    D.3.2Product code BMS-986016
    D.3.4Pharmaceutical form 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 INNrelatlimab
    D.3.9.2Current sponsor codeBMS-986016
    D.3.9.3Other descriptive nameAnti-LAG-3
    D.3.9.4EV Substance CodeSUB168199
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number11
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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: 4
    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 nameRelatlimab/ Nivolumab 1:3 Fixed Dose Combination
    D.3.2Product code BMS-986213
    D.3.4Pharmaceutical form 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 INNNIVOLUMAB
    D.3.9.1CAS number 946414-94-4
    D.3.9.2Current sponsor codeBMS-936558
    D.3.9.3Other descriptive nameMDX-1106, ONO-4538
    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 number12
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRelatlimab
    D.3.9.2Current sponsor codeBMS-986016
    D.3.9.3Other descriptive nameanti-LAG-3
    D.3.9.4EV Substance CodeSUB168199
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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: 5
    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 Yes
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 - 10ml vial - COMMERCIAL
    D.3.2Product code [BMS-936558]
    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 INNNIVOLUMAB
    D.3.9.1CAS number 946414-94-4
    D.3.9.2Current sponsor codeBMS-936558
    D.3.9.3Other descriptive nameMDX-1106, ONO-4538
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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: 6
    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 nameAnti-LAG-3 -8mL VIAL
    D.3.2Product code [BMS-986016]
    D.3.4Pharmaceutical form 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 INNrelatlimab
    D.3.9.2Current sponsor codeBMS-986016
    D.3.9.3Other descriptive nameanti-LAG-3
    D.3.9.4EV Substance CodeSUB168199
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    Neoplasms by site
    Neoplasie
    E.1.1.1Medical condition in easily understood language
    Neoplasms by site
    Neoplasie
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10061873
    E.1.2Term Non-small cell lung cancer
    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 21.1
    E.1.2Level LLT
    E.1.2Classification code 10065147
    E.1.2Term Malignant solid tumor
    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 21.1
    E.1.2Level PT
    E.1.2Classification code 10067946
    E.1.2Term Renal cell carcinoma
    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 21.1
    E.1.2Level LLT
    E.1.2Classification code 10053571
    E.1.2Term Melanoma
    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 10005003
    E.1.2Term Bladder cancer
    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 21.1
    E.1.2Level PT
    E.1.2Classification code 10067821
    E.1.2Term Head and neck cancer
    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 21.1
    E.1.2Level PT
    E.1.2Classification code 10017758
    E.1.2Term Gastric cancer
    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 10073071
    E.1.2Term Hepatocellular carcinoma
    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
    - Part A+B+A1:to assess safety, tolerability, DLTs, and MTD of
    BMS986016 alone and in combination with nivolumab in subjects with
    advanced solid tumors; to gather preliminary efficacy information of
    BMS986016 alone
    - Part C:to further establish safety and tolerability of BMS986016 in
    combination with nivo administered sequentially; to investigate the
    preliminary efficacy of BMS986016 in combination with nivo as
    measured by ORR, DCR and DOR in multiple tumor types
    - Part D: to assess safety and tolerability of more convenient dosing
    regimen; Part D1-Q2W: to demonstrate preliminary clinical evidence of
    the treatment effect, measured by ORR, as determined by BICR using RECIST v1.1 in advanced melanoma subjects; Part D1-Q4W: to confirm
    with Q4W dosing of BMS-986016 160 mg in combination with nivo 480
    mg, the safety and efficacy of the Q2W dosing of BMS-986016 80 mg in
    combination with nivo 240 mg, in advanced melanoma subjects
    ParteA+B+A1:valut.sicurez,tollerab,identif.tossic limitanti dose e maxdose toller.diBMS986016 somminis.da solo o in combinaz con nivo(in sogg aff da tumo solidi avanz);raccog.info prelimin.su efficac diBMS986016 somminist da solo.
    ParteC:stabilire ulteriorm. la sicurez e la tollerab diBMS986016+nivo somminis in maniera sequenz; studiare efficac prelimin diBMS986016 in combinaz con nivo misurata daORR,DCR,DOR(in multipli tipi di tumore).
    ParteD:valutare la sicurez e la tollerab di un regime di dosag più conven;ParteD1-Q2W:fornire prove clin prelimin effetto trattam, misur daORR, determinato da BICR median uso di RECISTv1.1(melanoma avanz);ParteD1-Q4W:conferm sicurez e effic del dosag di BMS986016 80mgQ2W in combinaz con nivo240mg (melanoma avanzato) con dosag di BMS986016 di160mgQ4W in combinaz con nivo480mg.
    ParteE:dimostrare che 480mg BMS986016+480mg nivoQ4W forniscono beneficio clin significativ. magg.(aumento ORR) rispetto a 160mg BMS986016+480mg dose nivoQ4W (melanoma).
    E.2.2Secondary objectives of the trial
    -To characterize PK of BMS986016 alone and with nivo
    -To investigate preliminary ORR and/or DCR of BMS986016 alone and
    with nivo in subjects with advanced solid tumors(A,B,Dose Esc)
    -To characterize immunogenicity of BMS986016 alone and with nivo
    -To assess effect of BMS986016 alone & with nivo on QTc(A,B)
    -To evaluate DOR, DCR, PFS rates at pre-specified time points based on
    BICR assessments using RECISTv1.1 in advanced melanoma subjects
    i)with, i)with a lack, i)regardless LAG-3 expression(D1, D2)
    -To evaluate ORR, DCR, DOR, PFS rates at pre-specified time points
    based on Investigator assessments using RECISTv1.1 in advanced
    melanoma subjects i)with, i)with a lack, i)regardless LAG-3
    expression(D1,D2)
    -To assess the 1Y and 2Y landmark OS in advanced melanoma
    subjects(D1, D2)
    For further secondary objectives, see protocol
    - Farmacocinetica di BMS-986016 in monoterapia o in combinazione con nivolumab
    - Tasso di risposta complessiva (ORR) preliminare e/o tasso di controllo della malattia (DCR) preliminare di BMS-986016 in monoterapia e in combinazione con nivolumab in soggetti affetti da tumori solidi in stadio avanzato (Parti A, B, dose esc).
    - Immunogeniticità di BMS-986016 in monoterapia o in combinazione con nivolumab
    - Effetto di BMS-986016 in monoterapia e in combinazione con nivolumab sull’intervallo QTc (A,B)
    - DOR, DCR, PFS rates a pre-specificati time points isulla base delle valutazioni del BICR utilizzando i criteri RECIST v. 1.1 in soggetti con melanoma avanzato i)con, i)con perdita, i)indipendentemente l’espressione di LAG-3 (D1, D2)
    - OS a 1Y e 2Y in soggetti con melanoma avanzato (D1, D2)
    Per ulteriori obiettivi secondari, cfr. protocollo
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives

    Pharmacogenetics
    Version: rev prot 08
    Date: 31/07/2017
    Title: For details, see protocol Section 5.7.11 Additional Research Collection
    Objectives: For details, see protocol Section 5.7.11 Additional Research Collection

    Pharmacogenomics
    Version: rev prot 08
    Date: 31/07/2017
    Title: For details, see protocol Section 5.7.11 Additional Research Collection
    Objectives: For details, see protocol Section 5.7.11 Additional Research Collection

    Farmacogenetica
    Versione: rev prot 08
    Data: 31/07/2017
    Titolo: Studio di Fase 1 di incremento della dose e espansione della coorte per valutare la sicurezza, la tollerabilit¿ e l¿efficacia dell¿anticorpo monoclonale anti-LAG-3 (BMS-986016) somministrato in monoterapia e in combinazione con l¿anticorpo monoclonale anti-PD-1 (Nivolumab, BMS-936558) nei tumori solidi in stadio avanzato. Sez 5.7.11 Additional Research Collection
    Obiettivi: La ricerca addizionale ¿ opzionale per tutti i partecipanti allo studio, tranne nei casi in cui la conservazione e/o la raccolta sia vietata dalle leggi locali o regolamenti, comitati etici, o requisiti istituzionali. La ricerca addizionale ha lo scopo di ampliare la capacit¿ traslazionale dell¿R&D di Bristol-Myers Squibb e sostenere scopi di ricerca ancora non definiti che miglioreranno la nostra conscenza della malattia e delle opzioni per il trattamento. Pu¿ anche essere utilizzata per supportare le richieste di autorit¿ competente per l'analisi ed il miglioramento dello sviluppo farmacodiagnostico allo scopo di fornire il trattamento pi¿ adatto a specifici pazienti. Questo pu¿ anche includere analisi genetiche/ genomiche volte a esplorare lo sviluppo della malattia, la progressione e la risposta al trattamento, ecc

    Farmacogenomica
    Versione: rev prot 08
    Data: 31/07/2017
    Titolo: Studio di Fase 1 di incremento della dose e espansione della coorte per valutare la sicurezza, la tollerabilit¿ e l¿efficacia dell¿anticorpo monoclonale anti-LAG-3 (BMS-986016) somministrato in monoterapia e in combinazione con l¿anticorpo monoclonale anti-PD-1 (Nivolumab, BMS-936558) nei tumori solidi in stadio avanzato.
    Sez 5.7.11 Additional Research Collection

    Obiettivi: La ricerca addizionale ¿ opzionale per tutti i partecipanti allo studio, tranne nei casi in cui la conservazione e/o la raccolta sia vietata dalle leggi locali o regolamenti, comitati etici, o requisiti istituzionali.
    La ricerca addizionale ha lo scopo di ampliare la capacit¿ traslazionale dell¿R&D di Bristol-Myers Squibb e sostenere scopi di ricerca ancora non definiti che miglioreranno la nostra conscenza della malattia e delle opzioni per il trattamento. Pu¿ anche essere utilizzata per supportare le richieste di autorit¿ competente per l'analisi ed il miglioramento dello sviluppo farmacodiagnostico allo scopo di fornire il trattamento pi¿ adatto a specifici pazienti. Questo pu¿ anche includere analisi genetiche/ genomiche volte a esplorare lo sviluppo della malattia, la progressione e la risposta al trattamento, ecc

    E.3Principal inclusion criteria
    •For Dose escalation: subjects with cervical, ovarian, bladder and CRC,
    head and neck, gastric and hepatocellular cancer naive to
    immunooncology agents; 1st line melanoma and 1st line/2nd line
    NSCLC; Renal Cell Carcinoma naive to IO; NSCLC progressing while on or
    after therapy with anti-PD1/anti-PDL-1 and melanoma subjects
    progressed while-on
    or after treatment with anti-PD1 or anti-PDL1 with or without anti-CTLA-
    4.
    •For Dose Expansion: all of the above in escalation except for cervical,
    ovarian and CRC
    •Progressed, or been intolerant to, at least one standard treatment
    regimen, except for subjects in 1st line cohorts.
    •ECOG performance status of 0 or 1
    •At least 1 lesion with measurable disease at baseline
    •Availability of an existing tumor biopsy sample (and consent to allow
    pre-treatment tumor biopsy)
    Per la dose escalation: soggetti affetti da cancro della cervice, dell’ovario, della vescica e del colon retto, testa collo, gastrico e epatocarcinoma cellulare naive all’immunoterapia; melanoma in prima linea e cancro al polmone non a piccole cellule in prima e seconda linea; carcinoma renale naive all’immunoterapia; cancro al polmone non a piccole cellule in pregressione durante o dopo trattamento con anti-PD1/anti PDL-1 e soggetti con melanoma in progressione durante o dopo trattamento con anti-PD1 o anti-PDL1 con o senza CTLA-4 e/o .
    Per la fase di espansione della dose: tutti i tipi di tumore citati sopra tranne il tumore della cervice, ovaio e colon retto.
    Soggetti in progression o intolleranti almeno a un regime di trattamento standard, tranne i soggetti nelle coorti di prima linea.
    ECOG performance status di 0 o 1.
    Almeno una lesione con malattia misurabile al baseline.
    Disponibilità di un esistente campione di biopsia tumorale (o consenso a effettuare una biopsia tumorale prima del trattamento se un campione non è già disponibile).
    E.4Principal exclusion criteria
    - Primary CNS tumors or solid tumors with CNS metastases as the only
    site of active disease
    - Autoimmune disease
    - Encephalitis, meningitis, or uncontrolled seizures in the year prior to
    informed consent
    - Uncontrolled CNS metastases
    Tumori primari del sistema nervoso centrale o tumori solidi con metastasi a livello del sistema nervoso centrale come unico luogo di malattia attiva
    Malattia autoimmune
    Encefalite , meningite, o convulsioni non controllate nel corso dell'anno precedente al consenso informato
    Metastasi incontrollata del sistema nervoso centrale
    E.5 End points
    E.5.1Primary end point(s)
    - Proportion of subjects with Adverse Events (AEs)
    - Proportion of subjects with Serious Adverse Events (SAEs)
    - Proportion of Deaths
    - Proportion of subjects with laboratory abnormalities in blood
    - Proportion of subjects with laboratory abnormalities in blood serum
    - Proportion of subjects with laboratory abnormalities in urine
    - Objective response rate (ORR)
    - Disease control rate (DCR)
    - Duration of response (DOR)
    - Number of AEs in the Broad Scope MedDRA Anaphylactic Reaction SMQ
    - Proportion of subjects with AEs leading to discontinuation of treatment
    - Proporzione di soggetti con eventi avversi (AE)
    - Proporzione di soggetti con eventi avversi seri (SAE)
    - Proporzione delle morti
    - Proporzione di soggetti con anomalie di laboratorio nel sangue
    - Proporzione di soggetti con anomalie di laboratorio nel siero
    - Proporzione di soggetti con anomalie di laboratorio nelle urine
    - Tasso di risposta obiettiva (ORR)
    - Tasso di controllo della malattia (DCR)
    - Durata della risposta (DOR)
    - Numero di eventi avversi nell'SMQ di reazione anafilattica MedDRA ad ampio spettro
    - proporzione di soggetti con eventi avversi che porta all'interruzione del trattamento
    E.5.1.1Timepoint(s) of evaluation of this end point
    Approximately Up to 3 years
    Approximately Up to 3 years
    Approximately Up to 3 years
    Approximately Up to 3 years
    Approximately Up to 3 years
    Approximately Up to 3 years
    Approximately 3 years
    Approximately 3 years
    Approximately 3 years
    Approximately 3 years
    Approximately Up to 3 years
    Approssimativamente fino a 3 anni
    Approssimativamente fino a 3 anni
    Approssimativamente fino a 3 anni
    Approssimativamente fino a 3 anni
    Approssimativamente fino a 3 anni
    Approssimativamente fino a 3 anni
    Circa 3 anni
    Circa 3 anni
    Circa 3 anni
    Circa 3 anni
    Approssimativamente fino a 3 anni
    E.5.2Secondary end point(s)
    - Maximum observed serum concentration (Cmax) of BMS-986016
    administered both alone and in combination with nivolumab
    - Time of maximum observed serum concentration (Tmax) of BMS-
    986016 administered both alone and in combination with nivolumab
    - Trough observed serum concentration (Ctrough) of BMS-986016
    administered both alone and in combination with nivolumab
    - Concentration at the end of a dosing interval (Ctau) [Eg: concentration
    at 336 hours] of BMS-986016 administered both alone and in
    combination with nivolumab
    - Area under the concentration-time curve in one dosing interval
    [AUC(TAU)] of BMS-986016 administered both alone and in combination
    with nivolumab
    - Total body clearance (CLT) of BMS-986016 administered both alone
    and in combination with nivolumab
    - Volume of distribution at steady state (Vss) of BMS-986016
    administered both alone and in combination with nivolumab
    - Effective elimination half-life that explains the degree of AUC
    accumulation observed (T-HALFeff AUC) of BMS- 986016 administered
    both alone and in combination with nivolumab
    - Effective elimination half-life that explains the degree of Cmax
    accumulation observed (T-HALFeff Cmax) of BMS-986016 administered
    both alone and in combination with nivolumab
    - Accumulation index; ratio of AUC(TAU) at steady state to AUC(TAU)
    after the first dose (AI_AUC) of BMS-986016 administered both alone and in combination with nivolumab
    - Cmax accumulation index; ratio of Cmax at steady state to Cmax after
    the first dose (AI_Cmax) of BMS-986016 administered both alone and in
    combination with nivolumab
    - Ctau accumulation index; ratio of Ctau at steady state to Ctau after the
    first dose (AI_Ctau) of BMS-986016 administered both alone and in
    combination with nivolumab
    - Degree of fluctuation (DF) or fluctuation index ([Cmax -
    Ctau]/Css,avg]) of BMS-986016 administered both alone and in
    combination with nivolumab
    - Immunogenicity measured by anti-drug antibody (ADA) for BMS-
    986016 (all participants) and nivolumab
    - QTc interval from centrally read electrocardiograms (ECGs)
    - Best overall response (BOR)
    - Objective response rate (ORR)
    - Disease control rate (DCR)
    - Duration of response (DOR)
    - Progression-free survival (PFS) rates
    - Overall survival (OS)
    - Number of AEs in the Narrow Scope MedDRA Anaphylactic Reaction
    SMQ
    1-Massima concentrazione osservata (Cmax) di BMS-986016 somministrato sia da solo che in combinazione con nivolumab
    2-Tempo della concentrazione massima osservato (Tmax) di BMS-986016 somministrato sia da solo che in combinazione con nivolumab
    3- Ctrough osservata di BMS-986016 somministrato sia da solo che in combinazione con nivolumab
    4- Concentrazione alla fine di un intervallo di dosaggio (Ctau) [Es .: concentrazione a 336 ore] di BMS-986016 somministrato sia da solo che in combinazione con nivolumab
    5-Concentrazione media su un intervallo di dosaggio [AUC (TAU) / tau] (Css, avg) di BMS-986016 somministrato sia da solo che in combinazione con nivolumab
    6-Area sotto la curva di concentrazione-tempo in un intervallo di dosaggio [AUC (TAU)] di BMS-986016 somministrato sia da solo che in combinazione con nivolumab
    7-Clearance totale (CLT) di BMS-986016 somministrato sia da solo e in combinazione con nivolumab
    8- Volume di distribuzione allo stato stazionario (Vss) di BMS-986016 somministrato sia da solo che in combinazione con nivolumab
    9- Emivita di eliminazione effettiva che spiega il grado di accumulo di AUC osservato (T-HALFeff AUC) di BMS-986016 somministrato sia da solo che in combinazione con nivolumab
    10- Emivita effettiva di eliminazione che spiega il grado di accumulo di Cmax osservato (T-HALFeff Cmax) di BMS-986016 somministrato sia da solo che in combinazione con nivolumab
    11-Indice di accumulo; Rapporto di AUC (TAU) allo stato stazionario con AUC (TAU) dopo la prima dose (AI_AUC) di BMS-986016 somministrata sia da solo che in combinazione con nivolumab
    12- indice di accumulo Cmax; Rapporto di Cmax allo stato stazionario con Cmax dopo la prima dose (AI_Cmax) di BMS-986016 somministrata sia da solo che in combinazione con nivolumab
    13- Indice di accumulo di Ctau; Rapporto di Ctau allo stato stazionario con Ctau dopo la prima dose (AI_Ctau) di BMS-986016 somministrata sia da solo che in combinazione con nivolumab
    14- Grado di fluttuazione (DF) o indice di fluttuazione ([Cmax -Ctau] / Css, avg]) di BMS-986016 somministrato sia da solo che in combinazione con nivolumab
    15- Immunogenicit¿ misurata con ADA per BMS-986016 (tutti i soggetti) e nivolumab
    16- intervallo QTc con revisione centralizzati degli elettrocardiogrammi (ECGs)
    17- migliore risposta globale (BOR)
    18- tasso di risposta obiettivo (ORR)
    19- tasso di controllo delle malattie (DCR)
    20- durata della risposta (DOR)
    21- sopravvivenza libera da malattia (PFS) – overall survival (OS) – numero di
    Eventi avversi nel Narrow Scope MedDRA Anaphylactic Reaction SMQ
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Approximately 2.3 years
    - Approximately 2.3 years
    - Approximately 2.3 years
    - Approximately 2.3 years
    - Approximately 2.3 years
    - Approximately 2.3 years
    - Approximately 2.3 years
    - Approximately 2.3 years
    - Approximately 2.3 years
    - Approximately 2.3 years
    - Approximately 2.3 years
    - Approximately 2.3 years
    - Approximately 2.3 years
    - Approximately 2.3 years
    - Approximately 2.3 years
    - Approximately 3 years
    - Approximately 3 years
    - Approximately 3 years
    - Approximately 3 years
    - Up to approximatively 3 years
    - Approximately 2 years
    - Approximately 3 years
    1- Circa 2,3 anni 2- Circa 2,3 anni 3- Circa 2,3 anni 4- Circa 2,3 anni 5- Circa 2,3 anni 6- Circa 2,3 anni 7- Circa 2,3 anni 8- Circa 2,3 anni 9- Circa 2,3 anni 10- Circa 2,3 anni 11- Circa 2,3 anni 12- Circa 2,3 anni 13- Circa 2,3 anni 14- Circa 2,3 anni 15- Circa 2,3 anni 16- Circa 3 anni 17- Circa 3 anni 18- Circa 3 anni 19- Circa 3 anni 20- Fino a circa 3 anni 21- Circa 2 anni 22- Circa 3 anni
    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 Yes
    E.6.7Pharmacodynamic Yes
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Dose Escalation and Cohort Expansion Study (Safety, Tolerability, and
    Efficacy)
    Dose Escalation and Cohort Expansion Study (Safety, Tolerability, and
    Efficacy)
    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 No
    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.8.2.4Number of treatment arms in the trial2
    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 EEA26
    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 Information not present in EudraCT
    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
    Canada
    Denmark
    Finland
    France
    Germany
    Italy
    Japan
    Netherlands
    Norway
    Spain
    Eswatini
    Switzerland
    United Kingdom
    United States
    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
    LPLV
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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 Yes
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 20
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 600
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 580
    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 state80
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 600
    F.4.2.2In the whole clinical trial 1200
    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)
    At the end of the study, BMS will not continue to supply study drug to subjects or Investigators
    unless BMS chooses to extend the study. The Investigator should ensure that the subject receives
    appropriate standard of care to treat the condition under study.
    Alla fine dello studio BMS non continuer¿ a fornire al farmaco in studio ai soggetti o investigatori salvo BMS scegliesse di estendere lo studio . Lo sperimentatore deve accertarsi che il soggetto riceva adeguata terapia standard per trattare la condizione in fase di studio.
    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 Decision2016-04-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-01-20
    P. End of Trial
    P.End of Trial StatusOngoing
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