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    The EU Clinical Trials Register currently displays   42567   clinical trials with a EudraCT protocol, of which   7008   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2016-001984-35
    Sponsor's Protocol Code Number:M16OPN
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-05-07
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2016-001984-35
    A.3Full title of the trial
    ‘Multicenter Phase 2 Study to Identify of the Optimal neo-Adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) and Personalized Response-driven Adjuvant Combination (PRADO extension cohort)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to find the best combination of ipilimumab and nivolumab before surgery and to determine whether a lymph node dissection is needed when patients respond well to immunotherapy
    A.3.2Name or abbreviated title of the trial where available
    OpACIN-neo and PRADO
    A.4.1Sponsor's protocol code numberM16OPN
    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
    B.4.2CountryNetherlands
    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 pointChristian Blank
    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+31205122570
    B.5.5Fax number+31205122572
    B.5.6E-mailc.blank@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.3.2Product 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-936558-01
    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.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 Yervoy
    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 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.3.9.4EV Substance CodeSUB29397
    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
    Patients with stage III melanoma
    E.1.1.1Medical condition in easily understood language
    Patients with skin cancer that has spread to the lymph nodes.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    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
    OpACIN-neo:
    Primary objectives:
    - To compare safety (immune related adverse events during the first 12 weeks) of three different neo-adjuvant combination schemes of ipilimumab + nivolumab
    - To compare radiological and pathologic response rates at week 6 of the three neo-adjuvant combination schemes

    PRADO extension cohort:
    Primary objectives:
    - To confirm the pathologic response rate (index lymph node, at week 6) of the winner neoadjuvant ipilimumab + nivolumab combination scheme identified in OpACIN-neo
    - To show that patients with pathologic complete response (pCR) or pathologic near complete response (pnCR) in the index lymph node can be spared safely a CLND without affecting their prognosis
    - To improve RFS at 24 months for patients achieving no pathologic response (pNR) by intensifying the subsequent adjuvant therapy


    E.2.2Secondary objectives of the trial
    OpACIN-neo:
    - To describe relapse free survival
    - To describe rate and type of late adverse events (up to 3 years)
    - To determine immune activating capacity of the alternative combination schemes

    PRADO extension cohort:
    - To confirm radiologic response rate at week 6 of the winner neo-adjuvant combination scheme identified in OpACIN-neo
    - To describe RFS and distant metastasis free survival (DMFS), for pCR, pnCR, pPR, and pNR patients at 2, 3 and 5 years
    - To describe event free survival (EFS) for the total population
    - To describe OS for the total population and for pCR/pnCR, pPR and pNR patients
    - To describe the grade 3/4 immune related adverse event rate within the first 12 weeks
    - To describe rate and type of late adverse events (up to 3 years)
    - To determine differences in surgical morbidity for only marked index lymph node resection versus CLND
    - To explore the immune activating capacity of the different response-driven treatment schemes

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Adults at least 18 years of age
    • World Health Organization (WHO) Performance Status 0 or 1
    • Cytologically and histologically confirmed resectable stage III melanoma with one or more macroscopic lymph node metastases (measurable according to RECIST 1.1), that can be biopsied, and no history of in-transit metastases within the last 6 months
    • No other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years
    • Patient willing to undergo triple tumor biopsies and extra blood withdrawal during screening and in case of relapse
    • No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1
    • No immunosuppressive medications within 6 months prior study inclusion
    • Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Neutrophils ≥1.5x109/L, Platelets ≥100 x109/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
    • Normal LDH
    • Women of childbearing potential (WOCBP) must use appropriate method(s) of contra-ception, i.e. methods with a failure rate of <1% per year when used consistently and correctly. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug
    • Women of childbearing potential must have a negative serum or urine pregnancy test
    (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of
    ipilimumab + nivolumab
    • Men who are sexually active with WOCBP must use any contraceptive method with a failure
    rate of less than 1% per year. Men receiving nivolumab and who are sexually active with
    WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last
    dose of investigational product
    • Women who are not of childbearing potential (i.e., who are postmenopausal), or surgically
    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.
    E.4Principal exclusion criteria
    • Distantly metastasized melanoma
    • Brain metastases
    • History of in-transit metastases within the last 6 months
    • No measurable lesion according to RECIST 1.1
    • Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy
    • Prior CTLA-4 or PD-1/PD-L1 targeting immunotherapy
    • Radiotherapy prior or post-surgery (except for non-responders in PRADO extension cohort;
    in this group is adjuvant radiotherapy allowed)
    • 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)
    • Allergies and Adverse Drug Reaction
    - History of allergy to study drug components
    - History of severe hypersensitivity reaction to any monoclonal antibody
    • Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events;
    • Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids;
    • 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)
    OpACIN-neo
    Primary endpoints:
    - Safety as measured by the frequency of grade 3/4 immune-related adverse events (during the first 12 weeks).
    - Response rate according to RECIST 1.1 at week 6
    - Pathologic response according to central revision (pathology of NKI).
    An interim analysis will be performed after 13 patients have been included in each arm (see 4.5), thus in total 39 patients have been included.

    PRADO extension cohort:
    Primary endpoints:
    - Pathologic response rate according to central revision (by a pathologist of the NKI or MIA) of the marked index lymph node
    - RFS at 24 months in patients achieving pCR or pnCR in their marked index lymph node and did not undergo CLND. RFS will be calculated from date of resection of the marked lymph node.
    - RFS at 24 months in patients with pNR and being subsequently treated with adjuvant nivolumab plus optional radiotherapy (or dabrafenib/trametinib if BRAFV600E positive and treatment is approved). RFS will be calculated from day of resection of marked lymph node.

    E.5.1.1Timepoint(s) of evaluation of this end point
    12 weeks after start treatment for patihological response
    24 months after lymph node resection for RFS
    E.5.2Secondary end point(s)
    OpACIN-neo
    Secondary endpoints:
    - Recurrence Free Survival (RFS)
    - Description of late adverse event (up to 3 years after treatment initiation) according to CTCAE v4.03
    - Description of associations of mutational load, RNA tumor signatures, and surface marker expression (DSP) with tumor immune infiltrates and response
    - Alteration in magnitude or breadth of the neo-antigen specific T cell responses in peripheral blood from baseline to surgery at week 6 in each 10 randomly chosen patients per arm.

    PRADO extension cohort:
    Secondary endpoints:
    - Response rate according to RECIST 1.1 at week 6
    - RFS at 2, 3 and 5 years
    - EFS at 2, 3 and 5 years
    - DMFS at 2, 3 and 5 years
    - OS at 2, 3 and 5 years
    - Grade 3/4 immune-related adverse event rate according to CTCAE v4.03 within the first 12 weeks
    - Surgical complication rates according to Clavien-Dindo surgical classification of only marked index lymph node resection vs. CLND
    - Description of late adverse event (up to 3 years after treatment initiation) according to CTCAE v4.03
    - Description of associations of mutational load, RNA tumor signatures (e.g. T cell, TiS, and IFN), and surface marker expression (DSP) with tumor immune infiltrates and pathologic response
    - Alteration in expansion/induction of tumor-resident TCR clones in peripheral blood from baseline to surgery at week.
    - Quality of life as measured by EORTC QLQ C30 and the melanoma and the surgery subscale of FACT-M

    E.5.2.1Timepoint(s) of evaluation of this end point
    At end of trial
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    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
    Denmark
    Netherlands
    Sweden
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    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 years7
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years9
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days14
    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: 160
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 160
    F.4.2.2In the whole clinical trial 200
    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 Decision2019-06-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-09-02
    P. End of Trial
    P.End of Trial StatusCompleted
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