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    Summary
    EudraCT Number:2015-003639-37
    Sponsor's Protocol Code Number:D4198C00003
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-01-30
    Trial results View 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 ConcernedUK - MHRA
    A.2EudraCT number2015-003639-37
    A.3Full title of the trial
    A Phase Ib and II Open-Label, Multi-Center Study of MEDI4736 Evaluated in Different Combinations in Patients with Metastatic Pancreatic Ductal Adenocarcinoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of MEDI4736, when used in combination with chemotherapy agents or AZD5069, as first or second line in metastatic Pancreatic Ductal Adenocarcinoma
    A.4.1Sponsor's protocol code numberD4198C00003
    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 SponsorAstraZeneca 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 supportAstraZeneca AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZenenca
    B.5.2Functional name of contact pointInformation Center
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018002369933
    B.5.6E-mailinformation.center@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 nameAZD5069 40mg film-coated tablet
    D.3.2Product code AZD5069
    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 INNAZD5069
    D.3.9.1CAS number 878385-84-3
    D.3.9.2Current sponsor codeAZD5069
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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 nameAZD5069 10 mg film-coated tablet
    D.3.2Product code AZD5069
    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 INNAZD5069
    D.3.9.1CAS number 878385-84-3
    D.3.9.2Current sponsor codeAZD5069
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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.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
    Adult patients (aged ≥18 years) with histologically or cytologically confirmed metastatic pancreatic ductal adenocarcinoma who are treatment naive or have tumor progression following prior standard first-line 5-FU-containing or gemcitabine-containing chemotherapy.
    E.1.1.1Medical condition in easily understood language
    Pancreatic Ductal Adenocarcinoma
    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 10033605
    E.1.2Term Pancreatic cancer 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
    1. Cohort 1: To assess the safety, tolerability of Medi4736 in combination with nab-paclitaxel + gemcitabine
    2. Cohort 2: To assess the safety, tolerability and ORR of MEDI4736 + AZD5069 in combination.
    E.2.2Secondary objectives of the trial
    1.To further assess the efficacy of MEDI4736 +AZD5069 in terms of DoR, DCR, PFS, PFS3, PFS6, OS, OS6, and OS12.

    2.To investigate the relationship between PD-L1 expression by IHC and efficacy parameters

    3.To investigate the immunogenicity of MEDI4736 in combination with AZD5069.

    4.To assess the PK of MEDI4736 and the combination of MEDI4736 and AZD5069.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age ≥18 years at the time of screening.
    2. Written informed consent and any locally required authorization obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
    3. Histologically or cytologically confirmed metastatic PDAC, no more than 1 prior systemic chemotherapy regimen or treatment-naïve patients
    4. Life expectancy ≥ 12 weeks.
    5. Eastern Cooperative Oncology Group 0 or 1
    6. At least 1 lesion, not previously irradiated, that can be accurately measured at
    baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have short axis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) scan and that is suitable for accurate repeated measurements
    -Patient should receive no more than 1 prior chemotherapy regimen or any other systemic therapy for recurrent/metastatic PDAC.
    7. Adequate organ and bone marrow function as defined below:
     Hemoglobin ≥9 g/dL
     Albumin ≥3 g/dL
     Absolute neutrophil count ≥1500/mm3
     Platelet count ≥100000/mm3
     Serum bilirubin ≤1.5 × the upper limit of normal (ULN). 
    ALT and AST ≤2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤5 × ULN
    Serum creatinine ≤1.5 mg/dL or calculated creatinine clearance ≥40 mL/min
    8. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female premenopausal patients
    9. Mandatory tumor biopsy at screening
    E.4Principal exclusion criteria
    1. Any concurrent chemotherapy, investigational product , biologic, or hormonal therapy for cancer treatment.
    2. Receipt of any investigational anticancer therapy within 28 days or 5 half-lives, whichever is shorter, prior to the first dose of study treatment.
    3. Concurrent enrollment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study.
    4. Receipt of last dose of an approved anticancer therapy within 21 days prior to the first dose of study treatment.
    5. Major surgical procedure (as defined by the Investigator) within 21 days prior to the first dose of IP
    6. Patients weighing less than 30 kg.
    7. History of leptomeningeal carcinomatosis
    8. Ascites requiring intervention
    9. Brain metastases or spinal cord compression
    10. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
    11. Current or prior use of immunosuppressive medication within 14 days before the first dose of MEDI4736. with exceptions that Intranasal, inhaled, or topical steroids; or local steroid injections; Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent; Steroids as premedication for hypersensitivity reactions and chemotherapy induced nausea and vomiting.
    12.Current or prior use of immunosuppressive medication within 14 days before the first dose of MEDI4736
    13. History of organ transplant that requires use of immunosuppressive agents.
    14. Active autoimmune disorders , or prior documented severe autoimmune or inflammatory disorders requiring immunosuppressive treatment
    - Prior exposure to immune-mediated therapy
    - Has received any potent and moderate cytochrome P450 (CYP)3A4 inhibitors, potent and moderate CYP3A4 inducers, P-glycoprotein substrates (digoxin and dabigatran), breast cancer resistance protein substrates (topotecan), sensitive CYP2B6 substrates (bupropion and efavirenz), warfarin and coumarin derivatives, or herbal supplements within 14 days of the first dose of study treatment
    15. Uncontrolled intercurrent illness
    16. Other malignancy within 5 years except for noninvasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin, prostate cancer or ductal carcinoma in situ of the breast that has/have been surgically cured
    17. Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥470 ms calculated from 3 ECG reports
    18. History of active primary immunodeficiency.
    19. Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus.
    20. Active infection including hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
    21. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
    22. Female patients who are pregnant or breastfeeding, or male or female patients of reproductive potential who are not employing an effective method of birth control (see Section 3.8).
    23. Known allergy or hypersensitivity to IP formulations or to other human monoclonal antibodies.
    24. Any condition that, in the opinion of the Investigator, would interfere with evaluation of IP or interpretation of patient safety or study results.
    25. Prior exposure to immune-mediated therapy or prior randomization or treament in previous MEDI4736 and/or tremelimumab clinical trials regardless of treatment arm assignment.
    E.5 End points
    E.5.1Primary end point(s)
    1. Objective response rate (Medi4736+AZD5069)
    2. Calculation or derivation of safety variables
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Objective response rate: RECIST assessment will be every 6 weeks (q6w ±7 days) for the first 48 weeks relative to the date of the first infusion, and q12w ±7 days thereafter until confirmed objective disease progression

    2. Data from all cycles of treatment will be combined in the presentation of the safety data
    E.5.2Secondary end point(s)
    1.Duration of Response, Disease control rate, Progression-free survival (PFS), Proportion of patients alive and PFS at 3, 6 & 12 months
    2. ORR, DoR, DCR, Os, and PFS across PD-L1 expression using Investigator assessments according to RECIST 1.1
    3.Presence of ADAs for MEDI4736
    4.Concentration of MEDI4736 & AZD5069 in blood and noncompartmental PK parameters
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-2 Objective response rate: RECIST assessment will be every 6 weeks (q6w ±7 days) for the first 48 weeks relative to the date of the first infusion, and q12w ±7 days thereafter until confirmed objective disease progression. Biopsy for PD-L1 expression analysis taken at screening and at Week 4

    3.Samples for immunogenicity assessment for MEDI4736 taken on day 1 of Cycles 1, 2, 3, 4, 7 and 3&6 months after last dose of IP

    4 PK (Serum/Blood - MEDI4736&AZD5069), taken on day 1 of Cycles 1, 2, 3, 4, 7. and 3 months after last dose of IP for MEDI4736 only
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA6
    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
    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
    Last subject last visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months11
    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: 7
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 12
    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 No
    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 state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 16
    F.4.2.2In the whole clinical trial 19
    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)
    After the final analysis, AstraZeneca will continue to supply open-label drug to patients receiving MEDI4736 + AZD5069 combination therapy up to completion of a patient’s treatment period
    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 Decision2017-03-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-03-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-07-03
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