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    The EU Clinical Trials Register currently displays   43846   clinical trials with a EudraCT protocol, of which   7282   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2015-000575-27
    Sponsor's Protocol Code Number:MK-3475-091-05
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-07-09
    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 ConcernedIreland - HPRA
    A.2EudraCT number2015-000575-27
    A.3Full title of the trial
    A randomized, phase 3 trial with anti-PD-1 monoclonal antibody pembrolizumab (MK-3475) versus placebo for patients with early stage NSCLC after resection and completion of standard adjuvant therapy (PEARLS)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Immunotherapeutic treatment with Pembrolizumab (antibody) in patients with early stage non-small cell lung cancer
    A.3.2Name or abbreviated title of the trial where available
    PEARLS
    A.4.1Sponsor's protocol code numberMK-3475-091-05
    A.5.4Other Identifiers
    Name:EORTCNumber:1416-LCG
    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 SponsorMerck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.
    B.1.3.4CountryUnited States
    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 supportMerck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.
    B.5.2Functional name of contact pointGlobal Clinical Trials Operations
    B.5.3 Address:
    B.5.3.1Street Address126 East Lincoln Avenue - P.O. Box 2000
    B.5.3.2Town/ cityRahway
    B.5.3.3Post codeNJ 07065
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1267 305 3850
    B.5.5Fax number+1267 305 6537
    B.5.6E-mailayman.samkari@merck.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 Yes
    D.2.1.1.1Trade name Keytruda® (pembrolizumab, MK-3475)
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme 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.3.4Pharmaceutical 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 INNPEMBROLIZUMAB
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK-3475
    D.3.9.3Other descriptive nameAnti-PD-1 monoclonal antibody
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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) Yes
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Stage IB (T ≥ 4 cm), II and IIIA NSCLC
    E.1.1.1Medical condition in easily understood language
    Early stage non small cell lung cancer after resection
    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.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To prospectively investigate whether adjuvant treatment with pembrolizumab after completion of radical surgery (lobectomy/pneumonectomy) with or without standard adjuvant chemotherapy for stage IB (T ≥ 4 cm) -II-IIIA NSCLC patients improves Disease Free Survival (DFS), as assessed locally by the investigator, compared to placebo in the PD-L1 strong positive subgroup (TPS≥50%) or overall population.

    Note: TNM stage (according to the 7th edition of the TNM classification for lung cancer).
    E.2.2Secondary objectives of the trial
    - To prospectively compare DFS as assessed by the investigator in the
    PD-L1 positive population (TPS≥1%);
    - To prospectively determine and compare OS in the PD-L1 strong positive and overall population;
    - To prospectively determine and compare OS in the PD-L1 positive population;
    - To prospectively determine and evaluate the Lung Cancer Specific Survival (LCSS) in the whole population irrespective of PD-L1 status;
    - To prospectively assess the safety of pembrolizumab after radical surgery followed by standard adjuvant chemotherapy.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Before patient registration, written informed consent for tumor testing must be given according to ICH/GCP and national/local regulations. For patients that accept to participate in the translational research, we recommend the informed consent for translational research be signed before registration step 1;
    - Pathological diagnosis of NSCLC confirmed at surgery, any histology is eligible;
    - Confirmed UICC v7 stage IB with T ≥ 4 cm, II-IIIA NSCLC after complete surgical resection (lobectomy, sleeve lobectomy, bi-lobectomy or pneumonectomy) as documented in the pathology report;
    - Resection margins proved microscopically free (R0); Resection margins are evaluated at the bronchial, venous and arterial stumps, peribronchial soft tissue, any peripheral margin near the tumor or of additionally resected tissue;
    - A systematic complete mediastinal lymph node dissection or a lobespecific mediastinal lymph node dissection (Appendix K) is recommended. At a minimum, the pathology and/or operative report must include the examination of at least two different mediastinal lymph node (N2) levels, one of which is the subcarinal (level 7) and the second of which is lobe-specific;
    - In the uncommon clinical situation where the surgeon thoroughly examines a particular mediastinal lymph node level and does not find any lymph nodes, that mediasintal lymph node level may be counted among the minimum two required levels. However, the surgeon must clearly document in the operative report or in a separate written statement that the lymph node level was explored and no lymph nodes were present. Normal appearing lymph nodes, if present, must be biopsied or/removed;
    - No extracapsular nodal extension of the tumor in resected mediastinal (N2) lymph nodes. Extracapsular tumor extension is permitted in resected N1 lymph nodes;
    - The highest mediastinal node removed can be positive for malignancy;
    - Carcinoma in situ can be present at bronchial margin
    - Availability of tumor sample obtained at surgical resection for PD-L1 Immunohistochemistry (IHC) expression assessment.
    - At least 18 years;
    - Adjuvant chemotherapy is not mandatory but considered for patients with stage IB (T ≥ 4 cm) and strongly recommended for stage II and IIIA, and will be administered according to national and local guidelines. Patients who received more than 4 cycles of adjuvant therapy are not eligible;
    - Patients not receiving adjuvant chemotherapy must be randomized and dosed with pembrolizumab/placebo within 12 weeks of their surgery date;
    - Participants who receive adjuvant chemotherapy must begin adjuvant chemotherapy within 12 weeks of the surgery date. Patients receiving adjuvant chemotherapy must be randomized and dosed with pembrolizumab/placebo at least 3 weeks but no more than 12 weeks from the last dose of chemotherapy (Day 1 of last cycle);
    - ECOG Performance status 0-1;
    - Adequate organ function performed within 10 days of treatment initiation;
    - Female patients with childbearing potential must have a negative urine or serum pregnancy test at screening (within 72 hours of first infusion of study medication)
    - If of childbearing potential, female patients must be willing to use two adequate barrier methods throughout the study, starting with the screening visit up to 120 days after last infusion of chemotherapeutic and investigational agents as specified in the protocol;
    - Male patients with a female partner(s) of child-bearing potential must agree to use two adequate barrier methods throughout the trial starting with the screening visit through 120 days after the last infusion of study treatment is received. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.
    - Female patients who are breast feeding should discontinue nursing prior to the first infusion of study treatment and until 120 days after the last study treatment;
    - Absence of severe comorbidities that in the opinion of the Investigator might hamper the participation to the study and/or the treatment administration;
    E.4Principal exclusion criteria
    - Evidence of disease at clinical examination and/or baseline radiological assessment on baseline assessment as documented by contrast enhanced chest/upper abdomen CT scan, brain CT/MRI and clinical examination within 8 weeks prior to the randomization date;
    - Prior or planned neoadjuvant or adjuvant radiotherapy and/or neoadjuvant chemotherapy for the current malignancy;
    - Prior treatment with an anti-PD-1, anti-PD-L1/2, anti- CD137, CTLA-4 modulators or any other immune-modulating agents; patients receiving live vaccine within 30 days prior to the first infusion of study treatment are not eligible;
    - Current participation in a interventional clinical trial or treatment with an investigational agent or use of an investigational device within 4 weeks of the first infusion of study treatment;
    - Known history of Human Immunodeficiency Virus (HIV) (known HIV 1/2 antibodies positive). Known active Hepatitis B or C. Active Hepatitis B is defined as a known positive HBsAg results. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay;
    - Chronic use of immunosuppressive agents and/or systemic corticosteroids or any use in the last 3 days prior to the first infusion of trial treatment;
    - History of interstitial lung disease (ILD) OR a history of (noninfectious) pneumonitis that required oral or IV steroids (other than COPD exacerbation) or current pneumonitis;
    - Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Any replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
    treatment and is allowed. Patients with hyperthyroidism or hypothyroidism but that are stable on hormone replacement are also allowed
    - History of a hematologic or primary solid tumor malignancy, unless in remission for at least 5 years. A pT1-2 prostatic cancer Gleason score < 6, superficial bladder cancer, non melanomatous skin cancer or carcinoma in situ of the cervix is eligible. Note: prior radiotherapy for another malignancy (breast cancer / lymphoma/germ cell tumors, etc.) is not an exclusion criterion, the same applies for prior anti-cancer systemic chemotherapy;
    - Previous allogeneic tissue/solid organ transplant;
    - Active infection requiring therapy;
    - Surgery or chemotherapy related toxicity ( non-hematological, toxicity resolved to grade 1 (see Appendix D), with the exception of alopecia, fatigue, neuropathy and lack of appetite /nausea);
    - Patients with two synchronous primary non-small cell lung cancers.
    E.5 End points
    E.5.1Primary end point(s)
    1. DFS in the PD-L1 strong positive sub-group;
    2. DFS in the overall population (co-primary endpoint).
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Every 12 weeks (± 2 weeks) during the 1st year after randomization, every 6 months (± 4 weeks) for the 2nd and 3rd year, yearly (± 4 weeks) for year 4 and 5. Thereafter at least yearly up to year 10
    2. Every 12 weeks (± 2 weeks) during the 1st year after randomization, every 6 months (± 4 weeks) for the 2nd and 3rd year, yearly (± 4 weeks) for year 4 and 5. Thereafter at least yearly up to year 10
    E.5.2Secondary end point(s)
    1. DFS in the PD-L1 positive population;
    2. OS in the overall population;
    3. OS in the PD-L1 strong positive subgroup;
    4. OS in the PD-L1 positive population;
    5. LCSS in the overall population;
    6. Toxicity according to CTCAE version 4.03.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Every 12 weeks (± 2 weeks) during the 1st year after randomization, every 6 months (± 4 weeks) for the 2nd and 3rd year, yearly (± 4 weeks) for year 4 and 5. Thereafter at least yearly up to year 10
    2. OS will be measured from the date of randomization until the date of death.
    3. OS will be measured from the date of randomization until the date of death.
    4. OS will be measured from the date of randomization until the date of death.
    5. LCSS will be measured from the date of randomization until the date of death (due to lung cancer specifically)
    6. Every 3 weeks during treatment and at 12 weeks after the last treatment
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) No
    E.8.2.2Placebo Yes
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA100
    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
    Switzerland
    Australia
    Canada
    Israel
    Japan
    Korea, Republic of
    Russian Federation
    United Kingdom
    Austria
    Belgium
    Czechia
    Denmark
    Estonia
    France
    Germany
    Greece
    Hungary
    Ireland
    Italy
    Latvia
    Netherlands
    Poland
    Portugal
    Slovenia
    Spain
    Türkiye
    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
    End of study occurs when all of the following criteria have been satisfied:
    1. The trial is mature for the analysis of the primary/co-primary endpoints as defined in the protocol
    2. The database has been fully cleaned and frozen for this analysis
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days12
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months4
    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 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: 727
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 453
    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 state22
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 651
    F.4.2.2In the whole clinical trial 1180
    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)
    Study drug will not be provided after a patient ends his/her participation in the trial.
    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 Decision2015-09-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-09-17
    P. End of Trial
    P.End of Trial StatusOngoing
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