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    Summary
    EudraCT Number:2019-002276-13
    Sponsor's Protocol Code Number:CA209-7DL
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-08-23
    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 ConcernedGermany - PEI
    A.2EudraCT number2019-002276-13
    A.3Full title of the trial
    Adjuvant nivolumab treatment in stage II high-risk melanoma – A randomized, controlled, phase III trial with biomarker-based risk stratification
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to test efficacy and safety of nivolumab-treatment in stage II melanoma patients with a high risk of relapse
    A.3.2Name or abbreviated title of the trial where available
    NivoMela
    A.4.1Sponsor's protocol code numberCA209-7DL
    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 SponsorUniversity Hospital Essen, Department of Dermatology
    B.1.3.4CountryGermany
    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
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Essen
    B.5.2Functional name of contact point Department of Dermatology
    B.5.3 Address:
    B.5.3.1Street AddressHufelandstraße 55
    B.5.3.2Town/ cityEssen
    B.5.3.3Post code45147
    B.5.3.4CountryGermany
    B.5.4Telephone number+492017234342
    B.5.5Fax number+492017235935
    B.5.6E-maildirk.schadendorf@uk-essen.de
    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
    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.3.2Product code BMS-936558
    D.3.4Pharmaceutical form Concentrate and solvent 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 nameNIVOLUMAB
    D.3.9.4EV Substance CodeSUB122750
    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
    Stage II melanoma arising from a primary cutaneous site after surgery therapy
    E.1.1.1Medical condition in easily understood language
    Melanoma arising from a primary cutaneous site
    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 LLT
    E.1.2Classification code 10025655
    E.1.2Term Malignant melanoma of skin
    E.1.2System Organ Class 100000004864
    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 is to determine efficacy of nivolumab in a biomarker-selected high-risk-enriched stage II melanoma patient population in comparison to control receiving observation only in a 2 (Arm A=nivolumab) :1 (Arm B=observation) randomization, as measured by Relapse-Free Survival (RFS) rates at 36 and 60 months.
    RFS is defined as the time from the date of registration until documented tumor recurrence date or date of death of any cause, whichever occurs first.
    E.2.2Secondary objectives of the trial
    Secondary objectives:
    1. To evaluate distant metastasis-free survival (DMFS), melanoma-specific survival (MSS) and overall survival (OS) rates at 36 and 60 months
    2. Safety / toxicity, i.e. all adverse events ≥ Grade 3 according to CTCAE Version 5.0 criteria, that are definitely, probably, or possibly related to the administration of the investigational agent
    3. To evaluate the clinical utility/decision impact of the MelaGenix GEP score in stratifying patients for adjuvant therapy

    In addition, patients not being selected as high-risk in the biomarker test (= Arm C) and who will be observed as in Arm B will be followed for RFS, DMFS and OS.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Central analysis of blood and tissue
    E.3Principal inclusion criteria
    1. Histologically confirmed diagnosis of stage II (AJCCv8) melanoma arising from a primary cutaneous site after surgery therapy
    2. Sentinel node biopsy (SNB) without detection of melanoma deposits
    3. Randomization not later than 12 weeks after SNB procedure
    4. Tumor tissue from primary tumor must be provided for biomarker analyses. In order to be randomized, a subject must be classified by MelaGenix risk analysis.
    5. Men and women at the age of 18 to 80 years
    6. Signed written, informed consent
    7. Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study
    8. Minimum life expectancy of five years excluding their melanoma diagnosis
    9. ECOG performance status of 0-1
    10. Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to randomization:
    o White blood cells (WBC) ≥ 2000/μL
    o Neutrophils ≥ 1500/μL
    o Platelets ≥ 100 x103/μL
    o Hemoglobin ≥ 9.0 g/dL
    o Serum creatinine ≤ 1.5xUL
    o Creatinine clearance (CrCl) ≥ 40mL/min (using the Cockcroft-Gault formula)
    o AST / ALT ≤ 3 x ULN
    o Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who may have total bilirubin < 3.0 mg/dL)
    11. Negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) for women of childbearing potential (WOCBP) within 72 hours prior to registration.
    Women will be considered to be of childbearing potential unless surgically sterilized (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or being post-menopausal for at least 24 months or being amenorrheic for > 12 months and follicle-stimulating hormone (FSH) levels ≥ 40 IU/L.
    12. WOCBP and male patients with partners of childbearing potential must agree to always use a highly effective form of contraception according to CTFG during the course of this study and for at least 5 months after last dose of study medication (in Arm A only).
    E.4Principal exclusion criteria
    1. History of primary uveal or mucosal melanoma
    2. No access to sufficient tumor tissue of primary tumor
    3. SNB procedure > 12 weeks before randomization
    4. Prior active malignancy within the previous 3 years except for locally curable cancers that have been apparently cured, such as: basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the prostate, cervix, or breast.
    Exception. Participants with a history of non-ulcerated cutaneous/acral primary melanoma <1 mm in depth with no nodal involvement are allowed in this trial.
    5. Prior or planned therapy with Interferon alpha, CTLA4 or PD-1 / PD L1 antibodies
    6. Use of any investigational or non-registered product (drug or vaccine) other than the study treatment
    7. Administration of live vaccines within 4 weeks before start of study therapy
    8. Any immunosuppressive therapy given within the past 30 days
    9. Active psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures
    10. Active immune deficiencies or significant autoimmune disease
    11. Serious cardiac, gastrointestinal, hepatic or pulmonary disease which would reduce life expectancy to less than five years
    12. Serious intercurrent illness, requiring hospitalization
    13. Other serious illnesses, e.g., serious infections requiring antibiotics or bleeding disorders
    14. The patient is known to be positive for Human Immunodeficiency Virus (HIV) or other active chronic infections (HBV, HCV) or has another confirmed or suspected immunosuppressive or immunodeficient condition
    15. Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.
    16. Hypersensitivity to the active substance or to any of the excipients
    17. Participation in another clinical study within the 30 days before registration
    18. For female patients: Pregnancy or breast-feeding
    19. For WOCBP and male patients with partners of childbearing potential: Refusal or inability to use effective means of contraception
    20. Lack of availability for clinical follow-up assessments
    21. Legal incapacity or limited legal capacity
    E.5 End points
    E.5.1Primary end point(s)
    Relapse / Recurrence-free survival (RFS) rate
    E.5.1.1Timepoint(s) of evaluation of this end point
    RFS rate at 36 and 60 months
    E.5.2Secondary end point(s)
    • Distant metastasis-free survival (DMFS) rate
    • Melanoma-specific survival (MSS) rate
    • Overall survival (OS) rate
    • AEs and clinical laboratory values
    • Clinical utility of the MelaGenix GEP score
    E.5.2.1Timepoint(s) of evaluation of this end point
    • DMFS rate at 36 and 60 months
    • MSS rate at 36 and 60 months
    • OS rate at 36 and 60 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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    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 Yes
    E.8.2.3.1Comparator description
    Randomization 2:1, either nivolumab or observation only
    E.8.2.4Number of treatment arms in the trial3
    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 concerned20
    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
    The start of the trial is defined as the first visit for the first patient entered. The end of study is defined as the last visit or phone call of the last patient, either at the end of study treatment or in the follow-up-period. A patient will be considered as lost to follow-up if no contact could be established for 3 consecutive time points.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    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: 250
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 124
    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 state374
    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)
    Following the end of treatment evaluation or the end of treatment for any other cause, patients will be treated and followed according to the guidelines of the German Cancer Society.
    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 Decision2020-04-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-04-07
    P. End of Trial
    P.End of Trial StatusOngoing
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