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    Summary
    EudraCT Number:2015-004005-16
    Sponsor's Protocol Code Number:D081KC00001
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-01-25
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2015-004005-16
    A.3Full title of the trial
    A Phase I/II Study of MEDI4736 (Anti-PD-L1 Antibody) in Combination with Olaparib (PARP inhibitor) in Patients with Advanced Solid Tumors
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase I/II Study of MEDI4736 in Combination with Olaparib in Patients with Advanced Solid Tumors
    A.4.1Sponsor's protocol code numberD081KC00001
    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 SponsorAstra Zeneca AB
    B.1.3.4CountrySweden
    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 supportAstra Zeneca AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstra Zeneca AB
    B.5.2Functional name of contact pointInformation Centre
    B.5.3 Address:
    B.5.3.1Street AddressSödertälje
    B.5.3.2Town/ citySödertälje
    B.5.3.3Post codeSE 151 85
    B.5.3.4CountrySweden
    B.5.6E-mailinformation.centre@astrazeneca.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 nameMEDI4736
    D.3.2Product code MEDI4736
    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 INNdurvalumab
    D.3.9.1CAS number 1428935-60-7
    D.3.9.2Current sponsor codeMEDI4736
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation 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 nameOlaparib
    D.3.2Product code AZD2281
    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 INNOlaparib
    D.3.9.1CAS number 763113-22-0
    D.3.9.2Current sponsor codeAZD2281
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product 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: 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 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 nameOlaparib
    D.3.2Product code AZD2281
    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 INNOlaparib
    D.3.9.1CAS number 763113-22-0
    D.3.9.2Current sponsor codeAZD2281
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product 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 RoleComparator
    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 AVASTIN
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Ltd.
    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 nameBevacizumab
    D.3.2Product code RO4876646/F02
    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 INNBEVACIZUMAB
    D.3.9.1CAS number 216974-75-3
    D.3.9.2Current sponsor codeRO4876646
    D.3.9.3Other descriptive namerhuMAb VEGF, anti-VEGF
    D.3.9.4EV Substance CodeSUB16402MIG
    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) 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 Yes
    D.3.11.13.1Other medicinal product typeRecombinant humanised monoclonal antibody
    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
    Initial stage cohort:
    SCLC germline BRCA mutated (gBRCAm) metastatic human epidermal growth
    factor receptor 2 (HER2) negative breast cancer (BC) gBRCAm platinum sensitive relapsed ovarian cancer (OvC) gastric cancer
    Second stage cohort:
    BRCAm platinum sensitive relapsed OvC non BRCAm platinum sensitive relapsed OvC
    Third stage cohort:
    HER2-negative, BRCAm BC
    HER2 negative, non BRCAm, Homologous Recombination Repair gene mutated (HRRm) BC non BRCAm, non HRRm triple negative BC
    E.1.1.1Medical condition in easily understood language
    Patients will have the following types of advanced or metastatic cancer:
    - small cell lung cancer
    - breast cancer
    - ovarian cancer
    - gastric cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10033130
    E.1.2Term Ovarian cancer NOS
    E.1.2System Organ Class 100000004864
    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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10027475
    E.1.2Term Metastatic breast cancer
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10041071
    E.1.2Term Small cell lung cancer stage unspecified
    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 assess the effect of MEDI4736 in combination with
    olaparib±bevacizumab in patients with selected advanced solid tumors.
    To assess the safety and tolerability of MEDI4736 in combination with
    olaparib (±bevacizumab) in patients with selected advanced solid
    tumors.
    E.2.2Secondary objectives of the trial
    To investigate the preliminary antitumor activity of MEDI4736 in comb with olaparib±bevacizumab in patients with selected advanced solid tumors.
    To determine plasma conc of olaparib after single and multiple dosing when given orally to patients alone and in combination with MEDI4736±bevacizumab.
    To characterize the PK, immunogenicity and pharmacodynamics of MEDI4736 after single dosing and multiple dosing when given intravenously to patients in combination with olaparib±bevacizumab.
    To characterize the PK and immunogenicity and pharmacodynamics of bevacizumab after single dosing and multiple dosing when given i.v. to patients in combination with MEDI4736 and olaparib.
    To evaluate candidate predictive biomarkers of treatment effect such as, but not limited to, PD-L1 expression
    Exploratory: To evaluate baseline measures and changes induced by olaparib alone and in combination with MEDI4736±bevacizumab, in peripheral blood, archival tumor, and tumor biopsies (frozen and fixed cores)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria are presented separately for each cohort of Modules 1
    to 10
    Small cell lung cancer cohort:
    Patients must have histologically or cytologically confirmed progressive
    metastatic or recurrent solid tumor (as defined below for each tumor
    type). To be enrolled in the SCLC cohort, only the tumor types and
    settings described below are allowed (see in the Protocol)
    At least 1 measurable lesion that can be accurately assessed at baseline
    by computed tomography (CT) (or magnetic resonance imaging [MRI]
    where CT is contraindicated) and is suitable for repeated assessment as
    per RECIST 1.1. The baseline scan must be obtained
    within 28 days prior to the first dose of olaparib. Biomarker-only disease
    is not considered evaluable.
    Breast cancer cohort:
    Patients must have histologically or cytologically confirmed progressive
    metastatic or recurrent solid tumor (as defined below for each tumor
    type). To be enrolled in the gBRCAm breast cancer cohort, only the
    tumor types and settings described below are allowed (see in the
    Protocol).
    At least 1 measurable lesion that can be accurately assessed at baseline
    by computed tomography (CT) (or magnetic resonance imaging [MRI]
    where CT is contraindicated) and is suitable for repeated assessment as
    per RECIST 1.1. The baseline scan must be obtained
    within 28 days prior to the first dose of olaparib. Biomarker-only disease
    is not considered evaluable.
    gBRCAm human epidermal growth factor receptor 2 (HER2)-negative
    breast cancer patients with metastatic or locally advanced disease,
    which is unresectable (or the patient is not a candidate for resection),
    may be first, second or third line but all patients must meet the following
    specific criteria:
    Must have confirmation of a germline mutation in BRCA1 or BRCA2 that
    is predicted to be deleterious or suspected deleterious (known or
    predicted to be detrimental/lead to loss of function).
    Must have previously received treatment with an anthracycline (eg,
    doxorubicin, epirubicin) unless contraindicated and/or a taxane (eg,
    paclitaxel, docetaxel) in either a neo-adjuvant/adjuvant or metastatic
    setting.
    gBRCAm ovarian cancer cohort:
    Patients must have histologically or cytologically confirmed progressive
    metastatic or recurrent solid tumor (as defined below for each tumor
    type). To be enrolled in the gBRCAm ovarian cancer cohort, only the
    tumor types and settings described below are allowed (see in
    the Protocol).
    At least 1 measurable lesion that can be accurately assessed at baseline
    by computed tomography (CT) (or magnetic resonance imaging [MRI]
    where CT is contraindicated) and is suitable for repeated assessment as
    per RECIST 1.1. The baseline scan must be obtained
    within 28 days prior to the first dose of olaparib. Biomarker-only
    disease is not considered evaluable.
    non-gBRCA ovarian cancer
    High grade serous ovarian cancer (including patients with primary
    peritoneal and/or fallopian tube cancer) with recurrent disease and:
    Previously received 1 or 2 previous lines of chemotherapy, including ≥1
    line of platinum-based therapy. NOTE: Adjuvant, neo-adjuvant, or
    maintenance treatment administered as part of a chemotherapy regimen
    would not be considered as separate line of therapy
    Gastric cancer cohort:
    Patients must have histologically or cytologically confirmed progressive
    metastatic or recurrent solid tumor (as defined below for each tumor
    type). To be enrolled in the gastric cancer cohort, only the tumor types
    and settings described below are allowed (see in the
    Protocol).
    At least 1 measurable lesion that can be accurately assessed at baseline
    by computed tomography (CT) (or magnetic resonance imaging [MRI]
    where CT is contraindicated) and is suitable for repeated assessment as
    per RECIST 1.1. The baseline scan must be obtained
    within 28 days prior to the first dose of olaparib. Biomarker-only disease
    is not considered evaluable.
    Metastatic or recurrent gastric adenocarcinoma (including
    gastroesophageal
    junction adenocarcinoma) that has progressed following first-line
    therapy, confirmed by imaging modalities:
    The first-line regimen must have contained at least a doublet 5-
    fluoropyrimidine and platinum based regimen.
    Capecitabine is an acceptable 5-fluoropyrimidine-containing agent.
    Relapse within 6 months of completion of adjuvant/neoadjuvant
    chemotherapy containing doublet 5-fluoropyrimidine and platinum based
    regimen is considered as first-line therapy.
    BRCAm Breast Cancer Expansion Cohort,Triple-negative Breast Cancer
    Triplet Cohort & HRRm breast cancer cohort
    Patients must have histologically or cytologically confirmed progressive
    metastatic or recurrent solid tumor (as defined in the Protocol for each
    tumor type).
    E.4Principal exclusion criteria
    Exclusion criteria are presented separately for each cohort in Modules 1
    to 9
    Small cell lung cancer cohort:
    Prior chemotherapy or other systemic anticancer therapy (eg, targeted
    biotherapy or hormonal agents) within 4 weeks prior to start of olaparib
    treatment; 6 weeks for nitrosoureas or mitomycin. Exceptions and
    treatments of particular importance are noted below (see Protocol)
    Radiation therapy within 4 weeks prior to start of olaparib treatment
    (includes radiation targeting bone metastases) or radionuclide
    treatment within 6 weeks of treatment start.
    Patients with mixed small cell and non-small cell lung cancer histology.
    Breast cancer cohort:
    Prior chemotherapy or other systemic anticancer therapy (eg, targeted
    biotherapy or hormonal agents) within 4 weeks prior to start of olaparib
    treatment; 6 weeks for nitrosoureas or mitomycin. Exceptions and
    treatments of particular importance are noted below (see the Protocol).
    Radiation therapy within 4 weeks prior to start of olaparib treatment (includes radiation targeting bone metastases) or radionuclide
    treatment within 6 weeks of treatment start.
    Patients with HER2-positive disease (3+ by immunohistochemistry [IHC]
    or in situ hybridization amplified ≥2.0).
    Patients cannot have received more than 2 prior lines of cytotoxic
    chemotherapy for metastatic disease. Prior treatments with hormonal
    therapy and non-hormonal targeted therapy are allowed and not counted
    as a prior line of cytotoxic chemotherapy. For the purposes of this
    protocol, the combination of an aromatase inhibitor and everolimus or
    palbociclib, are not considered cytotoxic chemotherapy.
    BRCA1 and/or BRCA2 variants that are considered to be non-detrimental
    (eg, "Variants of uncertain clinical significance" or "Variant of unknown
    significance" or "Variant, favor polymorphism" or "benign
    polymorphism" etc).
    gBRCAm ovarian cancer cohort:
    Prior chemotherapy or other systemic anticancer therapy (eg, targeted
    biotherapy or hormonal agents) within 4 weeks prior to start of olaparib
    treatment; 6 weeks for nitrosoureas or mitomycin. Exceptions and
    treatments of particular importance are noted below (see in the
    Protocol).
    Radiation therapy within 4 weeks prior to start of olaparib treatment
    (includes radiation targeting bone metastases) or radionuclide
    treatment within 6 weeks of treatment start.
    Patients with germline BRCA1 and/or BRCA2 variants that are
    considered to be non-detrimental (eg, "Variants of uncertain clinical
    significance" or "Variant of unknown significance" or "Variant, favor
    polymorphism" or "benign polymorphism" etc).
    non-gBRCA ovarian
    Patients with known germline BRCA1 and/or BRCA2 mutations, with the
    exception of variants of "uncertain clinical significance" or "Variant of
    unknown significance" or "Variant, favor polymorphism" or "benign
    polymorphism.
    Gastric cancer cohort:
    Prior chemotherapy or other systemic anticancer therapy (eg, targeted
    biotherapy or hormonal agents) within 4 weeks prior to start of olaparib
    treatment; 6 weeks for nitrosoureas or mitomycin. Exceptions and
    treatments of particular importance are noted below (see in the
    Protocol).
    Radiation therapy within 4 weeks prior to start of olaparib treatment
    (includes radiation targeting bone metastases) or radionuclide
    treatment within 6 weeks of treatment start
    For HER2-negative patients: More than 1 prior chemotherapy regimen
    (except for adjuvant/neoadjuvant chemotherapy with more than 6
    months wash-out period) for the treatment of gastric cancer in the
    metastatic or recurrent setting.
    For HER2-positive patients: More than 2 prior chemotherapy regimens
    (except for adjuvant/neoadjuvant with more than 6 months wash-out
    period) for the treatment of gastric cancer in the metastatic or recurrent
    setting.
    Intestinal obstruction or CTCAE grade 3 or grade 4 upper
    gastrointestinal bleeding within 4 weeks before the study entry
    BRCAm breast expansion cohort & HRRm breast cohort
    Prior chemotherapy or other systemic anticancer therapy (eg, targeted
    biotherapy or hormonal agents) within 4 weeks prior to start of study
    treatment; 6 weeks for nitrosoureas or mitomycin.
    Anti-hormonal treatment for breast cancer is allowed until 7 days prior
    to study treatment.
    Triple-negative Breast Cancer Triplet Cohort
    Prior chemotherapy or other systemic anticancer therapy (eg, targeted
    biotherapy or hormonal agents) within 4 weeks prior to start of study
    treatment; 6 weeks for nitrosoureas or mitomycin.
    Exposure to an investigational agent within 30 days or 5 half-lives
    (whichever is the longer) prior to start of study treatment is not allowed
    Prior receipt of biologics targeting T-cell co-regulatory proteins and/or
    immune checkpoints is not allowed
    Radiation therapy within 4 weeks prior to start of study treatment
    (includes radiation targeting bone metastases) or radionuclide
    treatment within 6 weeks of treatment start
    E.5 End points
    E.5.1Primary end point(s)
    Initial Stage Cohorts:
    Disease Control Rate (CR+PR+SD) based on modified RECIST 1.1 at 12
    weeks
    Secondary Stage Cohorts:
    BRCAm cancer expansion cohort: ORR (CR+PR) based on modified
    RECIST 1.1 assessed by Inv.
    Ovarian cancer triplet and doublet cohorts: DCR (CR+PR+SD) based on
    modified RECIST 1.1 at 24 weeks
    Third stage cohorts:
    BRCAm breast cancer expansion cohort: ORR (CR+PR) based on RECIST
    1.1 assessed by Inv.
    HRRm breast cancer and TNBC triplet cohorts: DCR (CR+PR+SD) based
    on RECIST at 16 weeks
    All cohorts:
    AEs vital signs, including blood pressure, pulse, ECG and laboratory
    findings (including clinical chemistry and hematology)
    irAEs: given the intended mechanisms of action of MEDI4736, particular
    attention will be given to AEs that may follow enhanced T-cell activation
    or other irAE
    Dose interruptions, dose reductions
    Causes of olaparib and MEDI4736 discontinuation
    Secondary and Third Stage Cohorts:
    Triplet cohorts only: Causes of bevacizumab discontinuation
    E.5.1.1Timepoint(s) of evaluation of this end point
    Initial Stage Cohorts: DCR (CR+PR+SD) based on modified RECIST 1.1 at
    12 weeks
    Secondary Stage Cohorts:
    BRCAm ovarian cancer expansion cohort: ORR (CR+PR) based on
    modified RECIST 1.1 assessed by Inv.
    Ovarian cancer triplet and doublet cohorts: DCR (CR+PR+SD) based on
    modified RECIST at 24 weeks
    Third Stage Cohorts:
    BRCAm breast cancer expansion cohort: ORR (CR+PR) based on RECIST
    1.1 assessed by Inv. every 8 weeks until objective disease progression
    and analyzed when all 80 patients have been followed for a min. of 24,
    40, 56, 80 and 104 weeks
    HRRm breast cancer and TNBC triplet cohorts: DCR (CR+ PR+SD) based
    on RECIST 1.1 at 16 weeks
    E.5.2Secondary end point(s)
    Initial Stage Cohorts:
    DCR at 28 weeks*
    ORR (CR+PR) based on modified RECIST 1.1*
    DoR based on modified RECIST 1.1*
    PFS based on modified RECIST 1.1*
    *Assessed by the investigator in all Initial Stage Cohorts. Also assessed
    by BICR in the gBRCAm ovarian cancer cohort
    Percentage change from baseline in tumor size at 12 weeks and 28
    weeks
    Best percentage change from baseline in tumor size
    Time to study treatment discontinuation
    Overall survival
    BRCAm ovarian cancer expansion cohort:
    DCR at 24 weeks and 56 weeks**
    DoR based on modified RECIST 1.1**
    PFS based on modified RECIST 1.1**
    **Assessed by the investigator and assessed by BICR
    ORR (CR+PR) based on modified RECIST 1.1 assessed by BICR
    Percentage change from baseline in tumor size at 24 weeks and 56
    weeks
    Best percentage change from baseline in tumor size
    TDT
    Overall survival
    Ovarian cancer triplet and doublet cohorts:
    DCR at 56 weeks
    DoR based on modified RECIST 1.1
    PFS based on modified RECIST 1.1
    ORR (CR+PR) based on modified RECIST 1.1 assessed by the Inv.
    Percentage change from baseline in tumor size at 24 and 56 weeks
    Best percentage change from baseline in tumor size
    TDT
    Overall survival
    Third Stage Cohorts:
    BRCAm breast cancer expansion cohort
    DCR and 16 and 24 weeks**
    DoR based on modified RECIST 1.1**
    PFS based on modified RECIST 1.1**
    **assessed by the Inv. and by BICR
    ORR (CR+PR) based on RECIST 1.1 assessed by BICR
    Percentage change from baseline in tumor size at 24 and 56 weeks
    Best percentage change from baseline in tumor size
    TDT
    Overall survival
    HRRm breast cancer and TNBC triplet cohorts:
    DCR at 24 weeks
    DoR based on RECIST 1.1
    PFS based on RECIST 1.1
    ORR (CR+PR) based on RECIST 1.1 assessed by the Inv.
    Percentage change from baseline in tumor size at weeks 24 and 56
    Best percentage change from baseline in tumor size
    TDT
    Overall survival
    E.5.2.1Timepoint(s) of evaluation of this end point
    Initial Stg Coh:DCR at 28weeks(w),DoR,PFS,ORR,OS* ,TDT**
    ,Percentage change(PC) from baseline in tumor at 12 and 28 w
    Second Stage Coh:BRCAm ov cancer expansion cohort:DCR at 24 and 56
    w,DoR, PFS, ORR, OS*,TDT**
    Ovn cancer triplet and doublet coh:DCR at 56
    w,DoR,PFs,ORR,OS*,TDT**,PC from baseline in tumor at w 24 and 56
    Third stg coh:BRCAm breast cancer exp cohort:DCR at w 16 and 24
    w,DoR, PFS, ORR, OS* ,TDT** ,PC from baseline in tumor at weeks 24
    and 56
    HRRm breast cancer and TNBC triplet coh:DCR at w 24,DoR, PFS,
    ORR,OS*,TDT**,PC from baseline in tumor at w 24 and 56
    *data obtained up until progression or last evaluable assessment in the
    absence of progression
    **data obtained up until treatment discontinuation or last recorded date on which the patient was know to be alive
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised 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 Yes
    E.8.1.7.1Other trial design description
    antitumor act of MEDI4736 in comb with ola in patients with metastatic or recurrent solid tumors
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA50
    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
    France
    Israel
    Korea, Republic of
    Netherlands
    Switzerland
    United Kingdom
    United States
    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
    The end of the study is defined as the date of the last visit of the last
    patient occurring when all patients have completed study therapy.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months7
    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: 798
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 88
    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 state31
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 433
    F.4.2.2In the whole clinical trial 886
    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)
    Patients are permitted to continue to receive study treatment following
    the end of the study if, in the opinion of the Investigator, they are
    continuing to receive benefit from treatment.
    After discontinuation of study treatment, the investigator will be at
    liberty to define further most appropriate anticancer treatment.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-01-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-03-14
    P. End of Trial
    P.End of Trial StatusOngoing
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