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    Summary
    EudraCT Number:2018-001757-27
    Sponsor's Protocol Code Number:MK-3475-859
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-14
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2018-001757-27
    A.3Full title of the trial
    A Phase 3, randomized, double-blind clinical study of pembrolizumab (MK-3475) plus chemotherapy versus placebo plus chemotherapy as first-line treatment in participants with HER2 negative, previously untreated, unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma (KEYNOTE-859)
    Studio di fase III, randomizzato, in doppio cieco volto a confrontare pembrolizumab (MK3475) più chemioterapia verso placebo più chemioterapia come trattamento in prima linea in soggetti con HER2 negativo, precedentemente non trattati, con adenocarcinoma gastrico o adenocarcinoma della giunzione gastro-esofagea non resecabile o metastatico (KEYNOTE -859)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Pembrolizumab/placebo plus chemotherapy as first-line therapy in participants with HER2 negative advanced gastric or GEJ adenocarcinoma
    Pembrolizumab/placebo più chemioterapia come terapia di prima linea nei partecipanti con adenocarcinoma gastrico o GEJ avanzato HER2 negativo
    A.3.2Name or abbreviated title of the trial where available
    -
    -
    A.4.1Sponsor's protocol code numberMK-3475-859
    A.5.4Other Identifiers
    Name:Other indentificationNumber:123 482
    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 CORP. UNA SUSSIDIARIA DI 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 Corp., 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 organisationMSD Italia Srl
    B.5.2Functional name of contact pointDivisione Ricerca Clinica
    B.5.3 Address:
    B.5.3.1Street AddressVia Vitorchiano, 151
    B.5.3.2Town/ cityRoma
    B.5.3.3Post code00189
    B.5.3.4CountryItaly
    B.5.4Telephone number0039090636191371
    B.5.5Fax number00390636380371
    B.5.6E-mailgcto.italy@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 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.3.9.2Current 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 number1
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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. - n. AIC: EU/1/15/1024/002
    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 name-
    D.3.2Product code [-]
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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: 3
    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 Cisplatino
    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 nameCisplatino
    D.3.2Product code [-]
    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 INNCISPLATINO
    D.3.9.1CAS number 15663-27-1
    D.3.9.2Current sponsor code-
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 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.IMP: 4
    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 Fluorouracile
    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 nameFluorouracile
    D.3.2Product code [-]
    D.3.4Pharmaceutical form Powder 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 INNFLUOROURACILE
    D.3.9.1CAS number 51-21-8
    D.3.9.2Current sponsor code-
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 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.IMP: 5
    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 Oxaliplatino
    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 nameOxaliplatino
    D.3.2Product code [-]
    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 INNOXALIPLATINO
    D.3.9.1CAS number 61825-94-3
    D.3.9.2Current sponsor code-
    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 Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 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.IMP: 6
    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 Capecitabina
    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 nameCapecitabina
    D.3.2Product code [-]
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCAPECITABINA
    D.3.9.1CAS number 154361-50-9
    D.3.9.2Current sponsor code-
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 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.IMP: 7
    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 Capecitabina
    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 nameCapecitabina
    D.3.2Product code [-]
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCAPECITABINA
    D.3.9.1CAS number 154361-50-9
    D.3.9.2Current sponsor code-
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 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
    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
    HER2 negative, previously untreated, unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma
    Adenocarcinoma gastrico o della giunzione gastroesofagea HER2 negativo, precedentemente non trattato, non resecabile o metastatico
    E.1.1.1Medical condition in easily understood language
    Gastric and gastric esophageal junction (GEJ) adenocarcinoma
    Adenocarcinoma gastrico e gastrico della giunzione esofagea (GEJ)
    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 LLT
    E.1.2Classification code 10071114
    E.1.2Term Metastatic gastric adenocarcinoma
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10058526
    E.1.2Term Oesophageal adenocarcinoma metastatic
    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 compare the overall survival (OS) of the participants following administration of pembrolizumab versus placebo when each is combined with chemotherapy
    - Per confrontare la sopravvivenza globale (OS) dei partecipanti dopo la somministrazione di pembrolizumab rispetto al placebo quando ciascuno è combinato con la chemioterapia
    E.2.2Secondary objectives of the trial
    - To compare the progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), as assessed by blinded independent central review (BICR), following administration of pembrolizumab versus placebo when each is combined with chemotherapy
    - To compare the objective response rate (ORR) per RECIST 1.1, as assessed by BICR, following administration of pembrolizumab versus placebo when each is combined with chemotherapy
    - To compare the duration of response (DOR) per RECIST 1.1, as assessed by BICR, following administration of pembrolizumab versus placebo when each is combined with chemotherapy in all participants and in participants with PD-L1-positive tumors (CPS >=1)
    - To evaluate the safety and tolerability of pembrolizumab plus
    chemotherapy versus placebo plus chemotherapy
    - Per confrontare la sopravvivenza libera da progressione (PFS) per i criteri di valutazione della risposta nei tumori solidi versione 1.1 (RECIST 1.1), come valutato dalla revisione centrale indipendente in cieco (BICR), in seguito alla somministrazione di pembrolizumab rispetto al placebo quando ciascuno è combinato con la chemioterapia
    - Confrontare il tasso di risposta obiettiva (ORR) per RECIST 1.1, valutato dal BICR, in seguito alla somministrazione di pembrolizumab rispetto al placebo quando ciascuna è combinata con la chemioterapia
    - Confrontare la durata della risposta (DOR) per RECIST 1.1, valutata dal BICR, a seguito della somministrazione di pembrolizumab rispetto al placebo quando ciascuna è combinata con la chemioterapia in tutti i partecipanti e nei partecipanti con tumori PD-L1 positivi (CPS>= 1)
    - Valutare la sicurezza e la tollerabilità di pembrolizumab plus
    chemioterapia contro placebo più chemioterapia
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Has histologically- or cytologically-confirmed diagnosis of locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma, with known PD-L1 expression status.
    2. Has HER2 negative cancer. HER2 negative is defined as: IHC (0, or 1+) or fluorescence in situ hybridization (FISH) negative (HER2:CEP17 ratio <2 with an average HER2 copy number <4.0 signals/cell). FISH can be replaced with locally available in situ hybridization (ISH) methods acceptable as per institutional guidelines (eg, DISH).
    3. Is Male or Female.
    4. Is at least 18 years of age at the time of signing the informed consent (or acceptable age according to local regulations, whichever is older).
    5. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 95 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 unless confirmed to be azoospermic
    (vasectomized or secondary to medical cause) as detailed below:
    • 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.
    6. A female participant is eligible to participate if she is not pregnant,
    not breastfeeding, and at least one of the following conditions applies A
    female participant is eligible to participate if she is not pregnant or
    breastfeeding, and at least one of the following conditions applies:
    • Is not a 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 and for at least 180 days after the last dose of
    chemotherapy or 120 days after the last dose of pembrolizumab,
    whichever is last, 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 before the first dose of study intervention.
    7. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research.
    8. Has measurable disease per RECIST 1.1 as assessed by investigator assessment. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
    9. Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalinfixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
    10. Has provided tumor tissue sample deemed adequate for PD-L1 biomarker analysis.
    11. Has provided tumor tissue sample for MSI biomarker analysis.
    12. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (within 3 days prior to the start of study intervention).
    13. Has adequate organ function, as defined in the protocol. Specimens must be collected within 10 days prior to the start-of-study intervention.
    1. presentano una diagnosi istologicamente o citologicamente confermata di adenocarcinoma gastrico metastatico o localmente avanzato non resecabile o della giunzione gastro-esofagea (GEJ), con stato di espressione di PD-L1 noto;
    2. hanno un tumore HER2-negativo.Lo stato HER2-negativo è definito come segue: negatività a IHC (0 o 1+) o al test dell’ibridazione fluorescente in situ (FISH) (rapporto HER2:CEP17 <2 con un numero di copie di HER2 medio <4,0 segnali/cellula). Il FISH può essere sostituito con metodi di ibridazione in situ (ISH) disponibili localmente e accettabili secondo le linee guida istituzionali (es. DISH).
    3. Sesso maschile o femminile;
    4. Almeno 18 anni di età al momento della firma del consenso informato (o un’età accettabile secondo le normative locali, a seconda di quale delle due sia maggiore).
    5. I partecipanti di sesso maschile possono partecipare se accettano il
    seguenti durante il periodo di intervento e per almeno 95 gg dopo
    l'ultima dose di chemioterapia:
    • Astenersi dal donare lo sperma
    IN PIÙ:
    • Astenersi dai rapporti eterosessuali come preferiscono e
    stile di vita abituale (astinenza a lungo termine e persistente) e d'accordo
    rimanere astinenti
    O
    Deve accettare di usare la contraccezione a meno che non sia confermato essere azoospermico (vasectomizzato o secondario a causa medica) come descritto di seguito:
    • Accetta di usare un preservativo maschile più il partner ne fa un altro
    metodo contraccettivo quando si hanno rapporti pene-vaginali con a
    WOCBP che non è attualmente incinta.
    6. Una partecipante donna può partecipare se non è incinta,
    non allatta al seno e si applica almeno una delle seguenti condizioni:
    • Non è WOCBP
    O
    • È WOCBP e utilizza un met contraccett altam efficace
    (con tasso di err <1% all'anno), con bassa dip dell'utente o
    astinenti dal rapporto eterosessuale come preferito e usuale
    stile di vita (astinente a lungo term e persist), durante il
    periodo di interv e per almeno 180 gg dopo ultima ds di
    chemio o 120 gg dopo ultima ds di pembro,
    a seconda di quale sia l'ultima, e si impegna a non donare uova (ovuli, ovociti) ad altri
    o congelare / conservare per uso personale ai fini della riproduz durante
    questo periodo. Lo sperim deve valutare il potenz di
    fallim del met contracc (cioè, non conform, iniziato di recente) in
    relaz alla 1a ds di interv in stu.
    - Un WOCBP deve avere test gravid altam sensibile negat ([urine
    o siero] come richiesto dalle norm loc) entro 24 h prima di
    1a ds interv stu
    7. Il partecipante (o il rappr legal riconosciuto, ove appl) fornisce il cons informato scritto per lo stu. Il partecip deve inoltre fornire il cons a partecip a future ricerche biomediche. Tuttavia, il soggetto può partecipare allo stu principale senza partecipare a future ricerche biomediche.
    8. Pz con malattia misurabile con i criteri RECIST versione 1.1, valutata dallo sperim. Le lesioni situate in un’area precedentem irradiata sono considerate misurabili se si evidenzia una progress in tali lesioni.
    9. Pz che hanno fornito campioni di tess tumorale presenti in arch o di nuova acquisiz di una lesione tumorale non irradiata in precedenza. È preferibile un blocco di tessuto tumorale fissato in formalina e incluso in paraffina (FFPE) rispetto al vetrino. È preferibile una biopsia di nuova acquisiz rispetto a un tessuto presente in archivio.
    10. Pz che hanno fornito un campione di tessuto tumorale considerato adeguato per l’analisi dei biomarcatori PD-L1.
    11. Pazienti che hanno fornito un campione di tessuto tumorale considerato adeguato per l’analisi dei biomarcatori MSI.
    12. Pazienti con performance status ECOG (Eastern Cooperative Oncology Group) pari a 0 o 1 (nei 3 giorni precedenti l’inizio del trattamento sperimentale)
    13. Pazienti con una funzionalità d’organo adeguata secondo quanto indicato nel Protocollo. Si dovrà procedere al prelievo dei campioni nei 10 giorni precedenti l’inizio del trattamento sperimentale.

    Per i restanti criteri di inclusione fare riferimento al Protocollo.
    E.4Principal exclusion criteria
    1. Has squamous cell or undifferentiated gastric cancer.
    2. Has had major surgery, open biopsy, or significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgery during the course of study intervention.
    3. Has pre-existing peripheral neuropathy >Grade 1.
    4. Is a WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization or treatment allocation.
    5. Has had previous therapy for locally advanced, unresectable and/or metastatic gastric/GEJ cancer. Participants may have received prior neoadjuvant or adjuvant therapy as long as it was completed at least 6 months prior to randomization.
    6. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PDL2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
    7. Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to randomization.
    8. Has received prior radiotherapy within 2 weeks prior to start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (<=2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
    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. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
    11. 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 to the first dose of study intervention.
    12. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
    13. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression) for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
    14. Has severe hypersensitivity (=Grade 3) to pembrolizumab and/or any of its excipients.
    15. 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.
    16. Has a history of (non-infectious) pneumonitis that required steroidsor has current pneumonitis.
    17. Has an active infection requiring systemic therapy.
    18. Has a known history of human immunodeficiency virus (HIV)infection.
    19. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined asHCV RNA [qualitative] is detected) infection.
    20. Has a known history of active tuberculosis.

    Please refer to the Protocol for the remaining exclusion criteria
    1. Carcinoma squamocellulare o gastrico indifferenziato;
    2. interventi chirurgici maggiori, biopsia aperta o lesione traumatica significativa nei 28 giorni prima della randomizzazione, oppure necessità di un intervento chirurgico maggiore nel corso del trattamento sperimentale.
    3. neuropatia periferica preesistente > Grado 1;
    4. donne potenzialmente fertili con risultato positivo al test di gravidanza sulle urine nelle 72 ore precedenti la randomizzazione (si veda l’Appendice 5). Se il test sulle urine è positivo o se non può esserne confermata la negatività, sarà necessario un test di gravidanza su siero.
    5. Precedente terapia per adenocarcinoma GEJ o gastrico metastatico o non resecabile localmente avanzato. I pazienti possono avere ricevuto una terapia neoadiuvante o adiuvante precedente purché sia stata completata almeno 6 mesi prima della randomizzazione;
    6. precedente terapia a base di un agente anti-PD-1, anti-PD-L1 o anti-PD-L2 o di un agente diretto contro un altro recettore delle cellule T co-inibitorio o stimolatorio (ad es. CTLA-4, OX-40, CD137);
    7. precedente terapia antitumorale sistemica tra cui agenti sperimentali nelle 4 settimane precedenti la randomizzazione.
    8. precedente radioterapia nelle 2 settimane precedenti l’inizio del trattamento sperimentale. I partecipanti devono essersi ripresi da tutte le tossicità correlate alle radiazioni, non devono necessitare di corticosteroidi e non devono avere avuto la polmonite da radiazione. È consentito un washout di 1 settimana per la radioterapia palliativa (<=2 settimane di radioterapia) per malattia non a carico del SNC (sistema nervoso centrale);
    9. Ha ricevuto una vaccinazione con vaccino vivo o attenuato nei 30 giorni precedenti la prima dose del trattamento in studio. La somministrazione di vaccini inattivati è consentita.
    10. Partecipazione attuale o pregressa a uno studio su un farmaco sperimentale o utilizzo di un dispositivo sperimentale nelle 4 settimane precedenti la prima dose del trattamento in studio.
    11. Diagnosi di immunodeficienza o trattamento cronico con steroidi sistemici (in dosi superiori a 10 mg/die di un equivalente del prednisone) o qualsiasi altra forma di terapia immunosoppressiva nei 7 giorni precedenti la prima dose del trattamento sperimentale;
    12. presenza di un ulteriore tumore maligno noto in progressione o che ha richiesto un trattamento attivo negli ultimi 5 anni.
    13. metastasi attive note a livello del SNC e/o meningite carcinomatosa. I partecipanti con metastasi cerebrali trattate precedentemente possono partecipare, purché siano radiologicamente stabili (ossia, senza evidenza di progressione) da almeno 4 settimane agli esami di imaging ripetuti (si noti che gli esami di imaging ripetuti devono essere eseguiti durante lo screening dello studio), siano clinicamente stabili e non richiedano il trattamento con steroidi almeno nei 14 giorni precedenti la prima dose di trattamento sperimentale;

    Per i restanti criteri di esclusione fare riferimento al Protocollo
    E.5 End points
    E.5.1Primary end point(s)
    - Overall survival (OS), defined as the time from randomization to death due to any cause
    - Progression-free Survival (PFS), defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first
    - Sopravvivenza globale (OS), definita come il tempo dalla randomizzazione alla morte dovuta a qualsiasi causa
    - Sopravvivenza libera da progressione (PFS), definita come il tempo dalla randomizzazione alla prima progressione della malattia documentata o morte per qualsiasi causa, a seconda di quale si verifichi per prima
    E.5.1.1Timepoint(s) of evaluation of this end point
    Overall survival (OS) = time from randomization to death due to any
    cause; Progression-free survival (PFS) = time from randomization to the first documented disease progression per RECIST 1.1 by (blinded independent central review (BICR) or death due to any cause, whicherver occurs first
    Sopravvivenza globale (OS) = tempo dalla randomizzazione alla morte dovuta a qualsiasi causa; Sopravvivenza libera da progressione (PFS) = tempo dalla randomizzazione allla prima progressione documentata della malattia per RECIST 1.1 di (in cieco revisione centrale indipendente (BICR) o decesso per qualsiasi causa, qualsiasi cosa si verifichi per prima
    E.5.2Secondary end point(s)
    - Objective response (OR), defined as Complete response (CR) or partial response (PR)
    - Duration of Response (DOR), defined as the time from first response (CR or PR) to subsequent disease progression, or death from any cause, whichever occurs first
    - Risposta obiettiva (OR), definita come risposta completa (CR) o risposta parziale (PR)
    - Durata della risposta (DOR), definita come il tempo dalla prima risposta (CR o PR) alla successiva progressione della malattia o morte per qualsiasi causa, a seconda di quale evento si verifichi per primo
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Objective Response Rate (ORR) = proportion of participants who have an overall response – complete response (CR) or partial response (PR);
    - Duration of Response (DOR) =time from first response (CR or PR) to subsequent disease progression or death from any cause, whichever occurs first
    - Tasso di risposta obiettiva (ORR) = percentuale di partecipanti che hanno una risposta globale - risposta completa (CR) o risposta parziale (PR);
    - Durata della risposta (DOR) = tempo dalla prima risposta (CR o PR) alla successiva progressione della malattia o morte per qualsiasi causa, a seconda di quale evento si verifichi per primo
    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) 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA103
    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 Information not present in EudraCT
    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
    Australia
    Brazil
    Canada
    Chile
    China
    Colombia
    Costa Rica
    Czechia
    Denmark
    France
    Germany
    Guatemala
    Hong Kong
    Hungary
    Ireland
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    New Zealand
    Peru
    Poland
    Russian Federation
    South Africa
    Spain
    Switzerland
    Taiwan
    Turkey
    Ukraine
    United Kingdom
    United States
    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
    The overall study ends when the last participant completes the last
    study-related telephone-call or visit, withdraws from the study, or is
    lost to follow-up (ie, the participant is unable to be contacted by the
    investigator).
    Lo studio complessivo termina quando l'ultimo partecipante completa l'ultima telefonata o visita relativa allo studio, si ritira dallo studio o è perso al follow-up (ovvero, il partecipante non può essere contattato dallo sperimentatore).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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: 455
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1087
    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 756
    F.4.2.2In the whole clinical trial 1542
    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
    Nessuno
    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 Decision2020-05-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-04-20
    P. End of Trial
    P.End of Trial StatusOngoing
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