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    Summary
    EudraCT Number:2019-002006-51
    Sponsor's Protocol Code Number:MK-3475-975
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-11-04
    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 number2019-002006-51
    A.3Full title of the trial
    A Randomized, Double-blind, Placebo-controlled Phase 3 Trial of Pembrolizumab (MK-3475) Versus Placebo in Participants with Esophageal Carcinoma Receiving Concurrent Definitive Chemoradiotherapy (KEYNOTE 975)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Placebo-controlled Trial of Pembrolizumab in Esophageal Carcinoma Participants Receiving Concurrent dCRT
    A.4.1Sponsor's protocol code numberMK-3475-975
    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
    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 organisation
    B.5.2Functional name of contact point
    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 namePEMBROLIZUMAB
    D.3.2Product code MK-3475
    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.3.9.4EV 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.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 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 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
    Esophageal Carcinoma
    E.1.1.1Medical condition in easily understood language
    Cancer of the esophagus
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10015366
    E.1.2Term Esophageal 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
    1. To compare definitive chemoradiotherapy (dCRT) + pembrolizumab to dCRT + placebo with respect to overall survival (OS) in participants with esophageal squamous cell carcinoma (ESCC), in participants whose tumors express programmed cell death-ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10, and in all participants
    2. To compare dCRT + pembrolizumab to dCRT + placebo with respect to event-free survival (EFS) per blinded independent central review (BICR) or biopsy in participants with ESCC, in participants whose tumors express PD-L1 CPS ≥10, and in all participants
    E.2.2Secondary objectives of the trial
    1. To evaluate the safety and tolerability profile of dCRT + pembrolizumab
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Is male or female and is at least 18 years of age on the day of providing documented informed consent with histologically or cytologically confirmed diagnosis of cTX N+ M0 or cT2-T4a NX M0 ESCC (as defined by AJCC 8th edition), GEJC, EAC, or histologically or cytologically confirmed diagnosis of cTX N+ M1 cervical or upper thoracic esophageal carcinoma with supraclavicular lymph node metastases only, is deemed suitable for dCRT (per requirement in the radiotherapy manual), has disease that is qualitatively evaluable upon radiographic assessment by local site Investigator, and is ineligible for curative surgery based on the documented opinion of a qualified medical/surgical/radiation oncologist.
    2. Is not be expected to require tumor resection during the course of the
    study
    3. Has an ECOG performance status of 0 to 1 within 3 days of the first
    dose of study intervention
    4. Is adequately nourished and hydrated per the Investigator's judgment. A feeding tube is acceptable to maintain adequate nourishment
    5. Has provided tumor tissue sample deemed adequate for PD-L1 and MSI biomarker analysis. The PD-L1 result must be determined as positive or negative by the central laboratory and the site notified of its adequacy. Study sites will be masked as to the PDL1 result. A repeat sample will be required if submitted sample is inadequate
    6. Has adequate organ function. Specimens must be collected within 14 days prior to the start of study treatment
    7. Male participants are eligible to participate if they agree to the following during the intervention period and through 90 days after the last dose of chemotherapy:
    - Refrain from donating sperm
    PLUS either:
    - Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
    OR
    - Must agree to use contraception as detailed below unless confirmed to be azoospermic (vasectomized or secondary to medical cause):
    Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant
    - If the contraception requirements in the local label for any of the study drugs is more stringent than the requirements above, the local label requirements should be followed.
    8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:
    - Is not a Woman of Childbearing Potential (WOCBP)
    OR
    - Is a WOCBP and using a 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 through 180 days after the last dose of chemotherapy or 120 days after the last dose of pembrolizumab, whichever is greater, 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 Investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention
    - A WOCBP must have a negative highly sensitive pregnancy test, urine or serum as required by local regulations, within 24 hours or 72 hours respectively before the first dose of study intervention.
    The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy
    - If the contraception requirements in the local label for any of the study
    drugs is more stringent than the requirements above, the local label
    requirements should be followed.
    9. Has (or legally acceptable representative if applicable) provided documented informed consent for the study. The participant may also provide consent/assent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research
    E.4Principal exclusion criteria
    1. Has direct invasion of tumor into adjacent organs such as the aorta or trachea (participants with T4b disease are not eligible for study participation) or has radiographic evidence of > 90 degree encasement or invasion of a major blood vessel, or of intratumoral cavitation.
    2. Has had major surgery other than for insertion of a feeding tube, open biopsy, or significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgery during study treatment. In addition, participants with gastric or esophageal fistulae are excluded from the trial.
    3. Has had weight loss of >20% in the previous 3 months
    4. Has had prior chemotherapy or RT for esophageal cancer
    5. Has had a myocardial infarction within the past 6 months. If the myocardial infarction occurred >6 months ago, participant may be included if no transient ischemia is evident and at the discretion of the Principal Investigator with input from a cardiologist
    6. Has symptomatic heart failure (ie, NYHA Class 2 or higher)
    7. Has a history or current evidence of any condition (eg, known deficiency of the enzyme dihydropyrimidine dehydrogenase, hearing impairment, etc), therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate (eg, any contraindication to the use of cisplatin, oxaliplatin, leucovorin or 5-FU), in the opinion of the treating Investigator
    8. Has received prior therapy with an antiPD-1, antiPD-L1, or antiPD-L2
    agent or with an agent directed to another stimulatory or coinhibitory Tcell
    receptor (eg, CTLA-4, OX-40, CD137).
    9. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention. Administration of killed vaccines is allowed.
    10. Has received any prior systemic anticancer therapy for esophageal cancer including investigational agents
    11. Has not recovered from all AEs due to previous non-anticancer therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible
    12. Is currently participating in or has participated in a study of an investigational agent for a condition or has used an investigational device within 4 weeks prior to the first dose of study intervention
    13. Has a diagnosis of immunodeficiency or is 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 the first dose of study drug
    14. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
    15. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, any of the study chemotherapy agents, or their excipients
    16. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
    17. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. Participant should be excluded if systemic steroids were required
    18. Has an active infection requiring systemic therapy
    19. Has a known history of human immunodeficiency virus (HIV) infection
    20. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection
    21. Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
    22. 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
    23. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
    24. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study intervention (180 days for participants receiving cisplatin who are breastfeeding)
    25. Has had an allogenic tissue/solid organ transplant
    E.5 End points
    E.5.1Primary end point(s)
    1. Overall Survival (OS)
    2. Event-free Survival (EFS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to ~72 months
    2. Up to ~60 months
    E.5.2Secondary end point(s)
    1. Number of participants with an adverse event (AE)
    2. Number of participants discontinuing study treatment due to an AE
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Up to ~15 months
    2. Up to ~12 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 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) 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA65
    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
    Argentina
    Brazil
    Canada
    Chile
    China
    Guatemala
    Hong Kong
    Japan
    Korea, Republic of
    Malaysia
    Peru
    Philippines
    Taiwan
    Thailand
    United States
    Estonia
    France
    Latvia
    Romania
    Germany
    Italy
    Denmark
    Hungary
    Portugal
    Russian Federation
    Turkey
    Ukraine
    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 years6
    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 years6
    E.8.9.2In all countries concerned by the trial months0
    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: 420
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 180
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 250
    F.4.2.2In the whole clinical trial 600
    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 Decision2019-11-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-12-11
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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