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    Summary
    EudraCT Number:2012-005019-14
    Sponsor's Protocol Code Number:12076
    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:2013-04-09
    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 number2012-005019-14
    A.3Full title of the trial
    The short term effects of an AKT inhibitor (AZD5363) on biomarkers of the AKT pathway and anti-tumour activity in a breast cancer paired biopsy study (STAKT Trial)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate the safety and effectiveness of a new anti cancer treatment - AZD5363 and assess its ability to affect levels of key proteins in cancer cells prior to the surgical removal of breast cancer.
    A.3.2Name or abbreviated title of the trial where available
    AKT inhibitor in breast cancer (STAKT study)
    A.4.1Sponsor's protocol code number12076
    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 SponsorUniversity of Nottingham
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCTAAC
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportAstraZeneca
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Nottingham
    B.5.2Functional name of contact pointProfessor J F R Robertson
    B.5.3 Address:
    B.5.3.1Street AddressGraduate Entry Medicine and Health Royal Derby Centre Uttoxeter Road
    B.5.3.2Town/ cityDerby
    B.5.3.3Post codeDE22 3DT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01332724881
    B.5.5Fax number01332724880
    B.5.6E-mailJohn.robertson@nottingham.ac.uk
    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 nameAZD5363
    D.3.2Product code AZD5363
    D.3.4Pharmaceutical form 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 INNAZD5363
    D.3.9.1CAS number 1143532-39-1
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number80 to 200
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    primary breast cancer
    E.1.1.1Medical condition in easily understood language
    early stage breast cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10057654
    E.1.2Term Breast cancer female
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    PRIMARY OBJECTIVE
    To compare the effect of three different dose levels of AZD5363 versus a placebo (dummy drug)on the reduction in the growth of cancer cells and the direct effect on selected biological markers of the AKT pathway of four and a half days treatment in oestrogen receptor positive breast cancers by measuring the biological changes in the tumour using the biomarkers outlined below:
    • pPRAS40
    • pGSK3b
    • Ki67
    Stage 1 will compare 480mg BD versus placebo.
    Stage 2 will compare 360mg BD versus 240mg BD.

    E.2.2Secondary objectives of the trial
    SECONDARY OBJECTIVES
    1) To compare the effect on the reduction in the growth of cancer cells and the direct effect on selected biological markers of the AKT pathway of four and a half days treatment of three different dose levels of AZD5363 versus placebo in oestrogen receptor positive breast cancers by measuring the biological changes in the tumour and circulation via measurement of:
    • Tumour pAKT
    • Platelet-rich plasma
    o Total and pPRAS40
    o Total and pGSK3b
    o Total and pAKT
    • Tumour tissue
    o Cleaved caspase 3
    o pS6
    o FOXO3a

    2) To measure tolerability and toxicity due to short term exposure to AZD5363.

    EXPLORATORY ANALYSES:
    It is envisaged that a number of tissue and blood based marker assays will be performed to assess if they provide any additional information on the activity of AZD5363 e.g.
    • Tissue markers e.g. PI3K, MAPK, HER2, PTEN, IGFR1, AR and total AKT

    • Blood markers – e.g. Autoantibodies to cancer associated antigens (especially those associated with
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Provision of written informed consent
    WHO performance status 0-1
    Able to swallow and retain oral medication
    Pre-menopausal (if surgically sterile or use acceptable contraception) or post-menopausal.
    Aged 18 years or over with histological confirmation of ER positive invasive breast carcinoma
    Stage 1/2/3 or Stage 4 with primary tumour in the breast amenable to biopsies
    scheduled to have chemotherapy (with or without surgery). New primary breast tumours (ipsi- or contra-lateral) despite prior endocrine treatment for an earlier primary breast tumour with at least 12 months interval between cessation of endocrine therapy and Visit 1 are eligible.
    Tumours large enough to provide sufficient tissue to be taken by core-cut or tru-cut biopsy.
    E.4Principal exclusion criteria
    1 Any prior treatment for breast cancer except new primary breast tumours despite prior endocrine treatment for an earlier primary breast tumour with at least 12 months interval between cessation of endocrine therapy and Visit 1.

    2 Known ER negative tumour.

    3 Female patients with histological confirmation of ER positive invasive breast carcinoma not scheduled to have chemotherapy (with or without surgery) based on tumour characteristics and local treatment protocols

    4 Exposure to potent inhibitors or inducers of CYP3A4 or CYP2D6 or substrates of CYP3A4 within 2 weeks before the first dose of study treatment (3 weeks for St John’s Wort).

    5 Clinically significant abnormalities of glucose metabolism as defined by any of the following:
     Diagnosis of diabetes mellitus type I or II (irrespective of management).
     Glycosylated haemoglobin (HbA1C) ≥8.0% at screening (64 mmol/mol) (conversion equation for HbA1C [IFCC-HbA1C (mmol/mol) = [DCCT-HbA1C (%) – 2.15] x 10.929)
     Fasting Plasma Glucose ≥ 7.0mmol/L (126 mg/dL) at screening. Fasting is defined as no caloric intake for at least 8 hours.
    6 Major surgery (excluding placement of vascular access) within 4 weeks before the first dose of study treatment.
    7 Spinal cord compression or brain metastases.
    8 As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
    9 Any of the following cardiac criteria:
     Mean resting corrected QT interval (QTc) >450 msec obtained from 3 consecutive ECGs.
     Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block.
     Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, potential for torsades de pointes, a history of congenital long QT syndrome, family history of long QT syndrome or a history of unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval. Further Information regarding this is given in Appendix 8.
     Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure NYHA Grade 2.
     Uncontrolled hypotension – SBP <90 mmHg and/or DBP <50 mmHg.
    10 Absolute neutrophil count <1.5 x 109/L.
    11 Platelet count <100 x 109/L.
    12 Haemoglobin <9 g/dL (<5.59 mmol/L). [Note: any blood transfusion must be >14 days prior to the determination of a haemoglobin ≥9 g/dL (≥5.59 mmol/L)].
    13 Alanine aminotransferase (ALT) >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases.
    14 Elevated Alkaline phosphatase (ALP) is not exclusionary if due to the presence of bone metastasis and liver function is otherwise considered adequate in the investigator’s judgement.
    15 Total bilirubin >1.5 times ULN if no liver metastases or >3 times ULN in the presence of liver metastases.
    16 Creatinine >1.5 times ULN concurrent with creatinine clearance <50 ml/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is >1.5 times ULN.
    17 Proteinuria >3+ on dipstick analysis
    18 Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD5363.
    19 History of hypersensitivity to active or inactive excipients of AZD5363 or drugs with a similar chemical structure or class to AZD5363.
    20 Current disease or condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
    21 Past medical history of interstitial lung disease, drug induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
    22 Evidence of dementia, altered mental status or any psychiatric condition that would prohibit understanding or rendering of informed consent.
    23 Previous allogeneic bone marrow transplant.
    24 Known immunodeficiency syndrome.
    25 Pregnant or lactating patients.

    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoints
    Changes in:
    • pPRAS40,
    • pGSK3b,
    • Ki67
    E.5.1.1Timepoint(s) of evaluation of this end point
    There will be a seamless transition from stage 1 to stage 2 with no break in patient recruitment. During stage 1 the biological markers will start to be measured. These biomarkers will be completed as swiftly as possible after stage 1 has finished. Following an analysis of these biomarker data obtained through stage 1 stage 2 will be stopped if there is a lack of significant knockdown by AZD5363 in terms of all the biomarkers included in the primary endpoints. Decisions will be made to proceed to recruit further patients to take part in stage 2 or not.
    E.5.2Secondary end point(s)
    1) Changes in alternative biological markers which relate to the AKT pathway.
    • Tumour pAKT
    • Tumour: cleaved caspase 3; pS6 (IHC); FOXO3a
    • Blood (platelet-rich plasma): Total and pPRAS40; Total and pGSK3b; Total and pAKT

    2) the tolerability of AZD5363 as measured by incidence and severity of adverse events

    Exploratory Endpoints:
    To assess blood and tissue based markers related to other cellular pathways – for example:
    • Blood: Autoantibodies to cancer-associated antigens in the AKT pathway
    • Tumour: PI3K, MAPK, HER2, PTEN, IGFR1, AR and total AKT

    Safety endpoints
    The duration of treatment (4 and a half days) will be short in comparison to prior and ongoing studies of the compound and the known side effect profile makes it unlikely that a study of this duration will be stopped for toxicity reasons. Nevertheless side effects will be collected according to the NCI-CTC criteria and there will be an analysis of toxicity at the end of Stage 1 and again at the end of Stage 2.

    Stopping rules and discontinuation
    Efficacy:
    As this is a study of the short-term (four and a half days) exposure of the compound aiming to measure the biological (not clinical) effects, there will be no stopping rules based on clinical efficacy or futility analyses.

    Biological endpoints:
    During stage 1 analysis all the biological markers which are listed as primary endpoints will commence during the recruitment period. These biomarker measurements will be completed as swiftly as possible after stage 1 has finished. Analyses of these biomarker data obtained through Stage 1 will be performed as swiftly as possible.
    Stage 2 will continue if the DSMC decide that significant knockdown by AZD5363 (as pre-defined) in terms of any the biomarkers included as primary endpoints has been achieved.
    Knockdown only in biomarkers in the Secondary endpoints will not be accepted as sufficient for the continuation of stage 2 unless there are substantive new data and even then only on the recommendation of the DSMC along with the joint agreement of the Investigators, the Steering Committee and AstraZeneca which is supplying the drug/placebo.
    If the DSMC concludes that no effect of the drug can be identified in Stage 1, the on-going enrolment to Stage 2 will be discontinued.


    Safety endpoints
    Serum haematology and biochemistry will be measured periodically during the course of the study and patients will be monitored for adverse events during that time and for at least 30 days after the end of treatment.

    Clinical adverse events will be collected and assessed as part of this study
    Timepoints:
    pre-treatment and after 4.5 days of treatment

    Safety endpoints
    Serum haematology and biochemistry will be measured periodically during the course of the study and patients will be monitored for adverse events during that time and for at least 30 days after the end of treatment.

    Clinical adverse events will be collected and assessed as part of this study

    E.5.2.1Timepoint(s) of evaluation of this end point
    Timepoints:
    pre-treatment and after 4.5 days of treatment

    Safety endpoints
    Serum haematology and biochemistry will be measured periodically during the course of the study and patients will be monitored for adverse events during that time and for at least 30 days after the end of treatment.

    Clinical adverse events will be collected and assessed as part of this study
    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 Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 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 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 concerned20
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    Last Visit Last Subject will define the end of the trial. Follow uyp for 30 days for pharmacovigilance
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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 years3
    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.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    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 No
    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 state150
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 0
    F.4.2.2In the whole clinical trial 0
    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)
    This not applicable as this treatment is intended to be of fixed duration (4.5 days)and given as pre-surgical therapy (prior to breast surgery) or pre-chemotherapy treatment (if patient is having chemotherapy). The normal standard of treatment and care will be given at the end of trial participation.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-03-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-05-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-02-21
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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