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    Summary
    EudraCT Number:2016-002940-17
    Sponsor's Protocol Code Number:N16NCI
    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:2016-09-19
    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 number2016-002940-17
    A.3Full title of the trial
    Nivolumab, Ipilimumab and COX2-inhibition in early stage colon cancer: an unbiased approach for signals of sensitivity
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    pre-operative nivolumab, ipilimumab and COC2-inhibition in colon cancer (NICHE)
    A.4.1Sponsor's protocol code numberN16NCI
    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
    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 organisationNKI-AVL
    B.5.2Functional name of contact pointDrs. M. Chalabi
    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+31205129111
    B.5.6E-mailm.chalabi@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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNivolumab
    D.3.2Product code BMS-936558
    D.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNivolumab
    D.3.9.2Current sponsor codeBMS-93655801
    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 AuthorisationNetherlands
    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.3.4Pharmaceutical form 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 codeBMS734016
    D.3.9.3Other descriptive nameMDX010
    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
    stage 2-3 adenocarcinoma of the colon
    E.1.1.1Medical condition in easily understood language
    colon carcinoma
    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 LLT
    E.1.2Classification code 10009957
    E.1.2Term Colon carcinoma
    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
    Primary Objective for the MSI cohort: To assess efficacy of neoadjuvant ipilimumab plus nivolumab in terms of disease-free survival.
    Primary objective for the MSS cohort: to explore the immune activating capacity of short-term immunotherapy with or without COX2-inhibition and identify underlying potential mechanisms of escape from the immune system.

    Additional exploratory secondary objectives for MSI cohort: expand current translational analyses, in terms of:
     RNA sequencing and inflammatory signatures to validate current findings;
     Functional analysis of immune cell infiltration and the difference with inflamed pMMR tumors pre- and post-treatment: why is there no pathological response in pMMR tumors showing immune activation?
     ctDNA analysis: can we predict complete and near-complete responses and if so; can we move to omitting surgery in this patient population?

    E.2.2Secondary objectives of the trial
    • To assess major pathological response rate (MPR, <10% viable tumor rest) and complete response rate;
    • To find biomarkers and evaluation strategies able to accurately assess complete and near-complete responses in order to pursue organ-sparing treatment (omission of surgery) in patient population,
    o Post-treatment CT-scans: can we use radiomics to accurately assess complete and near-complete response?
    o ctDNA analysis: can we use ctDNA to assess complete response and is there a difference between complete and near-complete response in terms of minimal residual disease on ctDNA, risk of relapse?
    • Translational analyses;
    o RNA sequencing and inflammatory signatures to validate current findings and identify predictors of response in pMMR tumors;
    o Analysis of immune cell infiltration and the difference with inflamed pMMR tumors pre- and post-treatment: why is there no pathological response in pMMR tumors showing immune activation?
    • To assess relapse free survival;
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Study population. In order to be eligible to participate in this study, a subject must meet all of the following criteria:
    • Stage 2-3 (>T3 and/or N+) adenocarcinoma of the colon (and upper rectum/rectosigmoid considered as non-rectal and not undergoing neoadjuvant treatment);
    • Colonoscopy must be performed after registration to obtain study-specific biopsies. If biopsies are not possible, patients cannot be included in the study;
    • WHO performance status of 0 or 1;
    • Screening laboratory tests must meet the following criteria and should be obtained within 7 days prior to randomization/registration: WBC > 2.0 x 10^9/L, ANC > 1.5x10^9/L, platelets > 100 x 10^9/L, Hemoglobin > 5.0mmol/L. Transfusion is allowed to obtain an adequate hemoglobin level. Liver function tests: total bilirubin
    < 1.5 upper limit of normal (ULN) (except for subjects with Gilbert syndrome, who can have total bilirubin <3.0 mg/dL); alkaline phosphatase <2.5 ULN; transaminases (ASAT/ALAT) <3 x ULN; LDH < 2 x ULN;
    • Creatinine clearance (Cockcroft-Gault) of >40 ml/min;
    • Women of childbearing potential (WOCBP)* must use appropriate method(s) of contraception. 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 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;
    • CT-scan must be performed within 28 days prior to registration;
    • No previous treatment with immune checkpoint inhibitors targeting including but not limited to CTLA-4, PD-1 or PD-L1;
    • No previous treatment with chemotherapy;
    E.4Principal exclusion criteria
    Study population. In order to be eligible to participate in this study, a subject must meet all of the following criteria:
    • (No) signs of distant metastases on CT-scan and physical examination;
    • No clinical obstruction;
    • No clinical symptoms or radiological suspicion of perforation;
    • For patients with MSS tumors: no current use of NSAIDs or COX2-inhibitors at registration and no active peptic ulcer, gastrointestinal bleeding, unstable ischemic heart disease of thrombus etiology or significant established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease;
    • No radiotherapy prior to or planned post-surgery radiotherapy;
    • Allergies and Adverse Drug Reaction:
    o No history of allergy to study drug components
    o No history of severe hypersensitivity reaction to any monoclonal antibody
    o No history of allergy or severe hypersensitivity to NSAIDs or COX2-I (MSS tumors);
    • No intercurrent illnesses, including but not limited to infections, unstable angina pectoris;
    • No underlying medical conditions that, in the Investigator’s opinion, will make the administration of the study drug hazardous or obscure the interpretation of toxicity determination of adverse events;
    • No positive test for hepatitis B virus surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection;
    • No history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);
    • No active autoimmune disease or a documented history of autoimmune disease, or other medical conditions requiring systemic steroid or immunosuppressive medications, except for subjects with vitiligo, diabetes mellitus type 1, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis or resolved childhood asthma/atopy not requiring systemic treatment;
    • No conditions requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease;
    • No live vaccines in the 4 weeks prior to inclusion;
    • No history of uncontrolled medical or psychiatric illness;
    • No psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule;
    No current pregnancy or breastfeeding;
    • No active malignancies other than disease under study within 3 years prior to inclusion, except for malignancies with a negligible recurrence rate (e.g. <10% in 5 years).
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint for the MSS cohort: analyses for efficacy and pathological response after immunotherapy in the MSS subgroup will be exploratory and hypothesis-generating, and will be used to guide future combinations within this study.
    Primary endpoint for the expanded MSI cohort: 3-year disease-free survival.

    Primary endpoint for the expanded MSI cohort: 3-year disease-free survival. A two-sided, one-sample logrank test calculated for a sample of 90 patients has 80% power at a 0.05 significance level to detect a 3-year DFS of 93% if the 3-year DFS in the historic control group is 82%, based on historical data.



    E.5.1.1Timepoint(s) of evaluation of this end point
    This calculation assumes that patients will be accrued within 4.5 years and the data will be analyzed 6 months after accrual of the last patient. The 4.5 years accrual takes into account the 3-year accrual within the current NICHE trial that has already taken.
    E.5.2Secondary end point(s)
    - To assess the major pathological response rate (MPR, <10% viable tumor rest) and complete response rate and whether response correlates with DFS; .
    - To find biomarkers and evaluation strategies able to accurately assess complete and near-complete responses in order to pursue organ-sparing treatment (omission of surgery) in this patient population in future trials::
    o Post-treatment CT-scans: can we use radiomics to accurately assess complete and near-complete response?
    o ctDNA analysis: can we use ctDNA to assess complete response and is there a difference between complete and near-complete response in terms of minimal residual disease on ctDNA and risk of relapse?
    - To expand current exploratory translational analyses, in terms of;
    o RNA sequencing and inflammatory signatures to find signatures predictive of response and possible escape mechanisms in non-responding tumors; .
    - Analysis of immune cell infiltration and the difference with inflamed pMMR tumors pre- and post-treatment: why is there no pathological response in pMMR tumors showing immune activation? And are there any differences between complete and near-complete responders?
    Primary readout will be the effect of therapy on intratumoral T-cell infiltration, CD4, CD8 infiltration and immune checkpoints upregulation in the time interval pre- and post-treatment in biopsies.
    - Immunogenic mutational load will be determined by tumor tissue DNA WES. Peripheral blood DNA WES will also be performed and used as a control for somatic mutation sorting (only genes relating to colon cancer and/or immune-related genes, deemed informational for this study, will be assessed).
    - Immune suppressive pathways, IFN-y induced gene expression and COX2 induced gene expression changes will be analyzed by use of RNA sequencing on pre- and post-therapy tissue;
    - Date of relapse, as determined by disease recurrence or disease-related death during follow-up after surgery. Follow-up will be performed according to local and/or national guidelines;
    - Fresh tissue for the generation of organoids or the use for other analyses using tumor digest, will be collected whenever possible.

    E.5.2.1Timepoint(s) of evaluation of this end point
    Pathology response: This calculation assumes that patients will be accrued within 4.5 years and the data will be analyzed 6 months after accrual of the last patient. The 4.5 years accrual takes into account the 3-year accrual within the current NICHE trial that has already taken.

    Other secondary: various timepoints
    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 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 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 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 years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 state130
    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)
    none
    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 Decision2016-09-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-11-25
    P. End of Trial
    P.End of Trial StatusOngoing
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