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    Summary
    EudraCT Number:2017-001123-53
    Sponsor's Protocol Code Number:MK3475-667
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-07-18
    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 number2017-001123-53
    A.3Full title of the trial
    An Open-label, Uncontrolled, Multicenter Phase II Trial of MK-3475 (Pembrolizumab) in Children and Young Adults with Newly Diagnosed Classical Hodgkin Lymphoma with Inadequate (Slow Early) Response to Frontline Chemotherapy (KEYNOTE 667).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase II trial of MK-3475 (pembrolizumab) in children and young adults with classical Hodgkin lymphoma
    A.4.1Sponsor's protocol code numberMK3475-667
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03407144
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/204/2016
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMerck Sharp & Dohme LLC
    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
    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
    B.5.2Functional name of contact pointGCTO
    B.5.3 Address:
    B.5.3.1Street Address126 East Lincoln Ave., P.O. Box 2000
    B.5.3.2Town/ cityRahway, NJ
    B.5.3.3Post code07065
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1732594 5269
    B.5.6E-mailakash.nahar@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.3.9.4EV 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 No
    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
    cHL in children and young adults
    E.1.1.1Medical condition in easily understood language
    Classical Hodgkin lymphoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10080208
    E.1.2Term Classical Hodgkin lymphoma
    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
    To evaluate the objective response rate (ORR) by International Working Group (IWG) criteria as assessed by blinded independent central review (BICR) [Cheson, B. D., et al 2007] of pembrolizumab in combination with chemotherapy in slow early responders (SERs) by risk group (low, high).

    E.2.2Secondary objectives of the trial
    1.To evaluate the rate of Positron Emission Tomography (PET) negativity, 2-year event-free survival (EFS) after study enrollment by IWG criteria as assessed by BICR, and overall survival (OS) of pembrolizumab in combination with chemotherapy in SERs by risk group
    2.To evaluate the exposure to radiation therapy (RT) and its associated toxicity in SERs by risk group
    3.To evaluate the rate of PET negativity per investigator assessment in Group 1 participants after completing 2 cycles of ABVD induction
    4.To evaluate the 3-year EFS and OS in rapid early responders (RERs) by risk group
    5.To evaluate serum TARC as a potential biomarker in SERs by risk group
    6.To evaluate the safety of pembrolizumab in combination with chemotherapy in SERs by risk group
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Must be male or female between the ages of 3 and 25 years inclusive
    on the day of signing informed consent/assent
    2. Group 1: Must have newly diagnosed, pathologically confirmed cHL at
    Stages IA, IB and IIA without bulky disease defined as the presence of
    any of the following:
    - Nodal area >6cm OR
    - Mass/thoracic diameter >one-third
    XML File Identifier: v6/QFlapiLYvqq9qbMSPxUS1Pnc=
    Page 11/25
    Group 2: Must have newly diagnosed, pathologically confirmed cHL at
    Stages IIEB, IIIEA, IIIEB, IIIB, IVA and IVB
    3. Must have measurable disease per investigator assessment. Target
    lesions situated in a previously irradiated area are considered
    measurable if progression has been demonstrated in such lesions.
    Measurable disease is defined as the existence of at least one
    measurable nodal lesion present, defined as a lymph node or nodal mass
    that is either >15 mm in longest diameter or >10 mm in short axis on
    anatomic imaging (ie, a diagnostic CT or MRI) and appropriate for
    reproducible measurements. A lesion that appears measurable, but is
    located in an area that was previously irradiated, can be considered
    measurable if it has shown growth since the completion of radiation
    4.Male participants are eligible to participate if they agree to the
    following during the
    interv period and for at least the time needed to eliminate each study
    interv after the last dose of study interv. The length of time required to
    continue contracep for each study intervention is:
    - Pembrolizumab: no contraception requir
    - Chemotherapy: refrain from donating sperm for 90 days after last dose
    of chemother
    PLUS either:
    - Be abstinent from heterosexual intercourse as their preferred and
    usual lifestyle and agree to remain abstinent
    OR
    - Uses contraception unless confirmed to be azoospermic documented
    from the site personnel's review of the participant's medical records,
    medical examination,
    or medical history interview as detailed below:
    o uses a male condom plus partner use of an additional contraceptive
    method when having penile-vaginal intercourse with a WOCBP who is
    not currently pregnant.
    o Contraceptive use by men should be consistent with local regulations
    regarding the methods of contraception for those participating in clinical
    studies.
    5. female participant is eligible to participate if she is not pregnant , not
    breastfeeding, and at least one of the following conditions applies:
    - Not a woman of childbearing potential (WOCBP)
    OR
    - Is a WOCBP and uses contraceptive method that is highly effective
    (with a failure rate of <1% per year), with low user dependency or be
    abstinent from heterosexual intercourse as their preferred and usual
    lifestyle (abstinent on a long-term and persistent basis), during the
    intervention period and for at least the time needed to eliminate each
    study intervention after the last dose of study intervention and agrees
    not to donate eggs (ova, oocytes) to others or freeze/store for her own
    use for the purpose of reproduction during this period. The length of
    time
    required to continue contraception for each study intervention is as
    follows:
    o Vinblastine and Vincristine: 30 days
    o Other Chemotherapies: 180 days
    o Pembrolizumab: 120 days. The investigator should evaluate the
    potential for contraceptive method failure (ie, noncompliance, recently
    initiated) in relationship to the first dose of study intervention.
    Contraceptive use by women should be consistent with local
    regulations regarding the methods of contraception for those
    participating in clinical
    studies. If the contraception requirements in the local label for any of
    the study
    interventions is more stringent than the requirements above, the local
    label requirements are to be followed.
    - has a negative highly sensitive pregnancy test (urine or serum as
    required by local regulations) within 24 hours before the first dose of
    study
    intervention. If a urine test cannot be confirmed as negative (eg, an
    ambiguous result), a serum pregnancy test is required. In such cases,
    the participant must be excluded from participation if the serum
    pregnancy result is positive.
    Abstains from breastfeeding during the study at least 120 days after
    study intervention for
    pembrolizumab and 180 days for chemotherapy, whichever is last.
    Has had her medical history, menstrual history, and recent sexual
    activity reviewed
    by the investigator to decrease the risk for inclusion of a woman with an
    early
    undetected pregnancy
    6. The participant (or legally acceptable representative if applicable)
    provides documented informed consent/assent for the study. The
    participant may also provide consent/assent for FBR. However the
    participant may participate in the main study without participating in
    FBR
    7. Must have a performance status as defined below:
    - Lansky Play-Performance Scale ≥50 for children up to 16 years of age
    - Karnofsky score ≥50 for participants ≥16 years of age
    8. Must have adequate organ function
    E.4Principal exclusion criteria
    1. Has undergone solid organ transplant at any time, or prior allogeneic
    hematopoietic stem cell transplantation within the last 5 years.
    Participants who have had allogeneic hematopoietic stem cell transplant
    greater than 5 years ago are eligible as long as there are no symptoms
    of graft-versus-host disease (GVHD)
    2. A WOCBP who has a positive urine pregnancy test within 24 hours
    before the first dose of study treatment. If the urine test is positive or
    cannot be confirmed as negative, a serum pregnancy test will be
    required. In such cases, the participant must be excluded from
    participation if the serum pregnancy result is positive
    3. Baseline left ventricular ejection fraction value <50% or shortening
    fraction of <27%
    4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL2
    agent or with an agent directed to another co-inhibitory T-cell
    receptor (ie, CTLA-4, OX-40, CD137) or has previously participated in a
    Merck pembrolizumab (MK-3475) clinical study
    5. Received prior systemic anti-cancer therapy, including investigational
    agent
    6.Has received a live or live-attenuated vaccine within 30 days before
    the first dose of study intervention. Administration of killed vaccines are
    allowed
    7. Has received an investigational agent or has used an investigational
    device within 4 weeks prior to study intervention administration
    8. Has a diagnosis of lymphocyte-predominant HL
    9. Has a diagnosis of immunodeficiency or is expected to be receiving
    chronic systemic steroid therapy (in dosing exceeding 10 mg daily of
    prednisone equivalent) or any other form of immunosuppressive therapy
    within 7 days prior to the first dose of pembrolizumab. The use of
    physiologic doses of corticosteroids (up to 5 mg/m2/day prednisone
    equivalent) may be approved after consultation with the Sponsor
    10. Has a known additional malignancy that is progressing or requires
    active treatment within the past 3 years
    11. Has radiographically detectable (even if asymptomatic and/or
    previously treated) central nervous system metastases and/or
    carcinomatous meningitis as assessed by local site investigator at the
    time of diagnosis
    12. Has severe hypersensitivity (≥Grade 3) to any study therapies
    including any excipients
    13. An active autoimmune disease that has required systemic treatment
    in past 2 years except replacement therapy (eg, thyroxine, insulin, or
    physiologic corticosteroid)
    14. Has a history of (non-infectious) pneumonitis/interstitial lung
    disease that required steroids or has current pneumonitis/interstitial
    lung disease.
    15. Has an active infection requiring systemic therapy
    16. Has a known history of human immunodeficiency virus (HIV)
    infection. No HIV testing is required unless mandated by local health
    authority
    17. Has a known history of Hepatitis B (defined as Hepatitis B surface
    antigen reactive) or known active Hepatitis C virus (defined as HCV RNA
    [qualitative] is detected) infection
    18. Has a history or current evidence of any condition, therapy, or
    laboratory abnormality that might confound the results of the study,
    interfere with the participant's participation for the full duration of the
    study, or is not in the best interest of the participant to participate, in
    the opinion of the treating investigator
    19. Has known psychiatric or substance abuse disorders that would
    interfere with cooperating with the requirements of the study
    20. Participants who have not adequately recovered from major surgery
    or have ongoing
    surgical complications.
    E.5 End points
    E.5.1Primary end point(s)
    Objective Response Rate (ORR) in SER Participants By Risk Group (Low, High) as Assessed by Blinded Independent Central Review (BICR)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to 5 years
    E.5.2Secondary end point(s)
    1.Rate of Positron Emission Tomography (PET) Scan Negativity in SER Participants By Risk Group (Low, High) After AVD or COPDAC-28 Chemotherapy
    2.Event-Free Survival (EFS) in SER Participants By Risk Group (Low, High) as Assessed by BICR
    3.Overall Survival (OS) in SER Participants By Risk Group (Low, High)
    4.Exposure to Radiotherapy (RT) in SER Participants By Risk Group (Low, High)
    5.Rate of PET Scan Negativity In Group 1 Participants After ABVD Induction Therapy
    6.EFS in Rapid Early Responder (RER) Participants By Risk Group (Low, High) as Assessed by Investigator
    7.OS in RER Participants By Risk Group (Low, High)
    8.Serum Thymus and Activation-Regulated Chemokine (TARC) Levels in SER Participants By Risk Group (Low, High)
    9.Number of SER Participants Experiencing an Adverse Event (AE) By Risk Group (Low, High)
    10.Number of SER Participants Discontinuing Study Treatment Due to AEs By Risk Group (Low, High)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1.Up to 5 years
    2.Up to 5 years
    3.Up to 5 years
    4.Up to 5 years
    5.Up to 5 years
    6.Up to 5 years
    7.Up to 5 years
    8.Up to 5 years
    9.Up to 5 years
    10.Up to 5 years
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    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 Yes
    E.6.11Pharmacogenomic Yes
    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 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.8.3 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 EEA28
    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
    Chile
    Colombia
    Guatemala
    New Zealand
    Peru
    Ukraine
    Hong Kong
    Australia
    Brazil
    Canada
    Israel
    Korea, Republic of
    Mexico
    Russian Federation
    South Africa
    Turkey
    United Kingdom
    United States
    Czechia
    France
    Germany
    Greece
    Italy
    Netherlands
    Slovakia
    Spain
    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 years9
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years9
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 340
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 17
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 266
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 57
    F.1.3Elderly (>=65 years) No
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 255
    F.4.2.2In the whole clinical trial 340
    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
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation European Network-Paediatric Hodgkin’s Lymphoma Study Group (EuroNet-PHL)
    G.4.3.4Network Country Germany
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-11-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-02-14
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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