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    The EU Clinical Trials Register currently displays   42564   clinical trials with a EudraCT protocol, of which   7007   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2019-001911-22
    Sponsor's Protocol Code Number:N19TVN
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-12-09
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2019-001911-22
    A.3Full title of the trial
    Neo-adjuvant T-VEC + NivolumabAnti-PD-1 combination therapy for resectable early metastatic (stage IIIB/C/D-IV M1a) melanoma with injectable disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study in melanoma patients with metastases in the lymph nodes and/or on/under the skin who will be treated with T-VEC and nivolumab before surgery.
    A.3.2Name or abbreviated title of the trial where available
    NIVEC
    A.4.1Sponsor's protocol code numberN19TVN
    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 SponsorAntoni van Leeuwenhoek Ziekenhuis
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBristol Myers Squibb (BMS)
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportAmgen
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAntoni van Leeuwenhoek Ziekenhuis
    B.5.2Functional name of contact pointStudy coordinator John Haanen
    B.5.3 Address:
    B.5.3.1Street AddressPlesmanlaan 121
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1066CX
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+310205129111
    B.5.6E-mailj.haanen@nki.nl
    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 Yes
    D.2.1.1.1Trade name Opdivo
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    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
    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.3.11 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 Yes
    D.2.1.1.1Trade name Imlygic
    D.2.1.1.2Name of the Marketing Authorisation holderAmgen Europe B.V.
    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 nameTalimogene Laherparepvec
    D.3.2Product code AMG 678
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntralesional use
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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 Yes
    D.3.11.3.5.1CAT classification and reference numberClassified as a Gene Therapy Medicinal Product EMA/CAT/451866/2012
    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 No
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    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
    Patients with early metastatic (stage IIIB/C/D/IV M1a (AJCC 8)) melanoma
    Patienten met vroeg gemetastaseerd (stadium IIIB/IIIC of IVM1a) melanoom
    E.1.1.1Medical condition in easily understood language
    Patients with skin cancer with metastases to the lymph nodes and/or on/under the skin
    Patienten met huidkanker met uitzaaiingen in de lymfeklieren en/of op/onder de huid
    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 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 21.1
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level SOC
    E.1.2Classification code 10029104
    E.1.2Term Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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
    To investigate if neo-adjuvant combination of talimogene laherparepvec and nivolumab will achieve a pathologic response rate of 45% complete responses (either ‘pathological complete response (pCR)’ or ‘pathological near complete response (near-pCR)’, in patients with stage IIIB/C/D/IV M1a (AJCC 8) melanoma
    E.2.2Secondary objectives of the trial
    - To investigate the rate of delays or failures (delays ≥14 days) to perform surgery
    - To investigate the effect of neo-adjuvant comabination of talimogene laherparepvec and nivolumab on relapse free survival (RFS)
    - To determine the safety of neo-adjuvant combination of talimogene laherparepvec and nivolumab
    - To acquire tumor tissue for prognostic and predictive biomarker research.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Adults at least 18 years of age
    - WHO performance score of 0 or 1
    - Cytologically or histologically confirmed diagnosis of stage IIIB/C/D/IVM1a (AJCC 8th edition) melanoma, eligible for surgical resection.
    - Subjects must have measurable disease according to RECIST 1.1 and must be a candidate for intralesional therapy with at least one injectable cutaneous, subcutane-ous or nodal melanoma lesion (≥ 10 mm in longest diameter) or with multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm.
    - Prior isolated limb perfusion (ILP) is allowed (≥ 12 weeks prior to enrollment)
    - Screening laboratory values must meet the following criteria:
    - WBC ≥ 2.0x10^9/L, Neutrophils ≥1.5x10^9/L, Platelets ≥100 x10^9/L, Hemoglobin ≥5.5 mmol/L, Creatinine ≤1.5x ULN, AST ≤ 1.5 x ULN, ALT ≤ 1.5 x ULN, Bilirubin ≤1.5 X ULN
    - LDH < 2 x ULN
    - Women of childbearing potential (WOCBP) must use highly effective method(s) of contraception (see paragraph 5.2) during T-VEC and nivolumab treatement and for a period of 5 months after the last dose of nivolumab.
    - Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to en-rollment and within 24 hours prior to the start of Nivolumab
    - Men receiving nivolumab and who are sexually active with WOCBP should use contraception during treatment and for a period of 7 months after the last dose of nivolumab
    - Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year.
    - Women who are not of childbearing potential (i.e., who are postmenopausal), or sur-gically sterile as well as azoospermic men do not require contraception
    - Patient is capable of understanding and complying with the protocol requirements and has signed the Informed Consent document.
    - Inhaled or topical steroids, and adrenal replacement steroid < 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
    - International normalization ratio (INR) or prothrombin time (PT) ≤1.5 x ULN, unless the subject is receiving anticoagulant therapy, in which case PT and partial thromboplastin time (PTT)/ activated PTT (aPTT) must be within therapeutic range of intended use of anticoagulants.
    E.4Principal exclusion criteria
    - Liver, Bone, Lung, Brain or other Visceral Metastases.
    - No measurable lesion according to RECIST 1.1
    - Prior radiotherapy for melanoma
    - Prior systemic cancer therapies, including, but not limited to anti-CTLA-4, anti-PD-1, anti-PD-L1
    - No other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years.
    - Patients will be excluded if they test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection
    - Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
    - Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity or adverse events. History or evidence of active autoimmune disease that requires high dose systemic treatment (ie, with use of disease modifying agents, corticosteroids or immuno-suppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Evidence of clinically significant immunosuppression such as the following:
    - Primary immunodeficiency state such as Severe Combined Immunodeficiency Disease.
    - Concurrent opportunistic infection.
    - Receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroid doses > 10 mg/day of prednisone or equivalent within 7 days prior to enrollment.
    - Active herpetic skin lesions or prior complications of HSV-1 infection (e.g., herpetic keratitis or encephalitis).
    - Requirement of intermittent or chronic systemic (intravenous or oral) treatment with an antiherpetic drug (e.g., acyclovir), other than intermittent topical use.
    - Previous treatment with talimogene laherparepvec or any other oncolytic virus.
    - Received live vaccine within 28 days prior to enrollment.
    - Subject has known sensitivity to talimogene laherparepvec or any of its components to be administered during dosing.
    - Female subject of childbearing potential who is unwilling to use highly effective method(s) of effective contraception during study treatment and through 5 months after the last dose of study medication (per protocol through 3 months after the last dose of talimogene laherparepvec and through 5 months after the last dose of nivolumab).
    - Sexually active subjects and their partners unwilling to use male or female latex condom to avoid potential viral transmission during sexual contact while on treatment and within 30 days after treatment with talimogene laherparepvec.
    - Subjects who are unwilling to minimize exposure with his/her blood or other body fluids to individuals who are at higher risks for HSV-1 induced complications such as immunosuppressed individuals, individuals known to have HIV infection, pregnant women, or infants under the age of 3 months, during talimogene laherparepvec treatment and through 30 days after the last dose of talimogene laherparepvec.
    - No Allergies and Adverse Drug Reaction

    - History of allergy to study drug components

    - History of severe hypersensitivity reaction to any monoclonal antibody
    - No underlying medical conditions that, in the Investigator's opinion, will make the ad-ministration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events;
    - No use of other investigational drugs before study drug administration 30 days and 5 half-times before study inclusion
    E.5 End points
    E.5.1Primary end point(s)
    Pathologic response according to central revision by pathology of NKI (complete response, near complete response (<10% vital tumor remaining))
    E.5.1.1Timepoint(s) of evaluation of this end point
    9 weeks after start of the neo-adjuvant treatment
    E.5.2Secondary end point(s)
    - Rate of delay of surgery >14 days and rate of failure to perform surgery de-fined as no surgery at all (due to PD or AE)
    - Relapse free survival (RFS) as defined from date of surgery until date of first replase (regardless of site)
    - Safety of neo-adjuvant combination of talimogene laherparepvec and nivolumab according to CTCAE v5.0
    - Description of possible prognostic and predictive biomarkers
    E.5.2.1Timepoint(s) of evaluation of this end point
    9 weeks after start of neo-adjuvant treatment
    During follow-up
    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 No
    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 Yes
    E.8.1.7.1Other trial design description
    Single arm
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 years3
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4
    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 state24
    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)
    After the trial, patients will be treated according to standard available treatment.
    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 Decision2019-12-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-06-04
    P. End of Trial
    P.End of Trial StatusOngoing
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