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    Summary
    EudraCT Number:2014-002613-31
    Sponsor's Protocol Code Number:009896QM
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-02-26
    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 ConcernedUK - MHRA
    A.2EudraCT number2014-002613-31
    A.3Full title of the trial
    A Phase Ib/IIa study of AZD2014 in combination with Selumetinib in patients with advanced cancers.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase Ib/IIa study of AZD2014 in combination with Selumetinib in patients with advanced cancers
    A.3.2Name or abbreviated title of the trial where available
    TORCMEK
    A.4.1Sponsor's protocol code number009896QM
    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 SponsorQueen Mary University of London
    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 supportAstraZeneca
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationQueen Mary University London
    B.5.2Functional name of contact pointChief Investigator
    B.5.3 Address:
    B.5.3.1Street AddressCentre for Experimental Cancer Medicine
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeEC1M 6BQ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02078823444
    B.5.6E-mailp.schmid@qmul.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 nameAZD2014
    D.3.2Product code AZD2014
    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.3.9.1CAS number 1009298-59-2
    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 number10mg tablets to 50mg tables
    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: 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 nameSelumetinib
    D.3.2Product code AZD6244
    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.3.9.1CAS number 606143-52-6
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Triple-Negative Breast Cancer
    Non-squamous Small Cell Lung Cancer
    Squamous Cell Lung Cancer
    E.1.1.1Medical condition in easily understood language
    Breast cancer
    Lung cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Selumetinib is a drug that acts by blocking a protein called MEK, which has been linked to the development and growth of multiple cancers. AZD2014 is a drug that blocks a protein called mTOR that is involved in the growth and spread of cancer. Blocking the action of either MEK or mTOR alone may slow down or stop the cancer growing. Combining both drugs may make the cancer more sensitive than if Selumetinib or AZD2014 are used alone and as such make this treatment more effective.
    The principal research question for this study is to establish the feasible dose levels and regimens of AZD2014 and selumetinib when given in combination. Also, we will assess the clinical activity as measured by disease control rate, of AZD2014 and selumetininb in combination.
    E.2.2Secondary objectives of the trial
    The secondary objectives are as follows:
    1) Assess the clinical activity as measured by patient response rate and change in tumour size of AZD2014 in combination with selumetinib
    2) Establish the safety and tolerability of AZD2014 in combination with selumetinib
    3) Determine the impact on the pharmacokinetics of AZD2014 and selumetinib when administered together
    4) Assess progression-free survival, duration of response and overall survival of patients treatment with AZD2014 and selumetinib
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Written informed consent prior to admission to this study
    2) Age ≥18 years
    3) ECOG performance status 0 or 1
    4) Life expectancy ≥ 12 weeks
    5) Patients must have been at least one lesion, not previously irradiated, that can be measured accurately at baseline as ≥10mm in the longest diameter (except lymph nodes which must have short axis ≥15mm) with computerised tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeatede measurements
    6) Radiological or clinical evidence of disease progression
    7) Formalin fixed, paraffin embedded tumour sample from the primary or recurrent cancer must be available for central testing
    8) Adequate haematologic and end organ function, defined by laboratory results obtained within 14 days prior to the first study treatment
    9) Female patients of child-bearing potential are eligible, provided they have a negative serum or urine pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception beginning 2 weeks before the first dose of investigational product and for 30 days after the final dose of investigational product. Male patients must agree to use appropriate contraception during the trial and for 3 months afterwards

    Criteria unique to the Dose Escalation Part (Phase 1b part):
    1) Histologically or cytologically advanced solid tumour; the study will be limited to
    a) tumour types with frequent activation of MAPK and/or PI3K pathways (pancreatic, thyroid, endometrial, renal, breast or ovarian carcinoma, colorectal cancer, NSCLC or melanoma
    b) tumours with known alteration in ≥1 gene involved in PI3K/AKT/mTOR or Ras/MEK pathway signalling, such as KRAS, NRAS, BRAF, PIK3CA, PTEN, AKT, LKB1, EGFR, FGFR, HER2, MET, RET, KIT
    2) Metastatic or locally advanced disease, which is refractory to conventional treatment or for which no conventional therapy exists; locally recurrent disease must not be amenable to resection with curative intent

    Criteria unique to the lung cancer dose expansion cohorts (phase IIa part):
    1) Histologically confirmed non-small cell lung cancer
    2) Stage III disease that is unsuitable to radio-chemotherapy or Stage IV disease or recurrent NSCLC; recurrent disease must not be amenable to resection or radical radiotherapy with curative intent
    3) Prior chemotherapy and/or, if indicated/accessible, EGFR-directed or ALK-directed therapy for advanced disease

    Criteria unique to the triple-negative breast cancer dose expansion cohort (phase IIa):
    1) Histologically confirmed triple negative breast cancer
    2) Metastatic or locally recurrent disease; locally recurrent disease must not be amenable to resection with curative intent
    3) Prior chemotherapy for advanced disease
    E.4Principal exclusion criteria
    1) Symptomatic CNS involvement or CNS involvement requiring steroid therapy; patients with treated brain metastases that are asymptomatic and have been clinically stable for 1 month will be eligible for protocol participation
    2) Prior chemotherapy, biological therapy, radiation therapy, immunotherapy, other anticancer agents and any investigational agents within 14 days of starting study treatment
    3) Any unresolved toxicity > CTCAE Grade 1 from previous anti-cancer therapy
    4) Current refractory nausea and vomiting, chronic gastrointestinal disease or inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of the study medication
    5) Significant cardiovascular disease
    6) QTc prolongation defined as a QTc interval >470msecs
    7) Concomitant medications known to prolong QT interval
    8) Patients receiving concomitant immunosuppressive agents or chronic systemic corticosteroids for ≥28 days at the time of study entry
    9)Evidence of interstitial fibrotic lung disease (bilateral, diffuse, parenchymal lung disease)
    10) Clinically significant abnormalities of glucose metabolism
    11) Opthalmological conditions as follows:
    a) Intra-ocular pressure >21mmHg, or uncontrolled glaucoma
    b) Current or past history of central serous retinopathy or retinal vein occlusion
    12) Exposure to potent or moderate inhibitors or inducers of CYP3A4/5 if taken within the stated washout period before the first dose of study treatment
    13) Exposure to potent or moderate inhibitors or inducers of CYP2C8 within the stated washout periods before the first dose of study treatment
    14) Exposure to sensitive or narrow therapeutic range substrates of the drug metabolising enzymes CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters Pgp and BCRP within the appropriate wsh-out period before the first dose of study treatment
    15) Active second malignancy (except non-melanomatous skin cancer); active secondary malignancy is defined as a current need for cancer therapy or a high possibility of recurrence during the study
    16) Any evidence or uncontrolled systemic disease, active infection, active bleeding diatheses or renal transplant, including any patient known to have hepatitis B, hepatitis C or human immunodeficiency virus (HIV)
    17) Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that in the investigators opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent
    18) Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol
    19) Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational drug within 30 days prior to study entry


    Criteria specific to dose expansion cohorts:
    1) Prior treatment with PI3K inhibitors, AKT inhibitors, mTOR inhibitors or MEK, Ras or Raf inhibitors
    2) Prior radiotherapy to the indicator lesion(s); newly arising lesions in previously irradiated areas are accepted
    E.5 End points
    E.5.1Primary end point(s)
    Phase Ib:
    Dose Limiting toxicities.

    Phase IIa:
    Disease control rate defined as complete (CR) or partial response (PR) or stable disease (SD) mantained ≥12 weeks (RECIST v1.1).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase Ib: DLTs will be assessed at the end of each escalation cohort

    Phase IIa: Will be assessed at baseline and every 6 weeks from Day 1 of cycle 1.
    E.5.2Secondary end point(s)
    Phase Ib:

    - Single dose and/or multiple dose AZD2014 PK parameters including Tmax, Cmax, and AUC
    - Single dose and/or multiple dose selumetinib PK parameters including Tmax, Cmax, and AUC.

    Phase IIa:
    - ORR, defined as the number of patients with measurable disease at baseline with CR or PR (as assessed by the site radiologist, using RECIST 1.1) divided by the number of patients at risk
    -Average change (%) in tumour size at 12 weeks compared to baseline as assessed by RECIST v1.1; tumour size is defined as the sum of the diameters of the target lesions.
    -Safety and tolerability as assessed by Adverse Events (AEs) (CTCAE, v4.03).
    -Single dose and/or multiple dose of AZD2014 and selumetinib PK parameters (e.g. including Tmax, Cmax, and AUC)
    - PFS defined as the time from the date of registration to the date of first documented tumour progression (RECIST v1.1) or death from any cause, whichever occurs first.
    -Duration of response defined as the time from first documentation of CR or PR to disease progression (RECIST v1.1) or death from any cause, whichever occurs first.
    -Overall survival defined as the time from date of registration to the date of death due to any cause.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Phase Ib: Blood sampling for PK will be carried out at pre-defined time-points during Cycle 1.

    Phase IIa:
    - ORR will be assessed at baseline and every 6 weeks from Day 1 of cycle 1.
    - Average change in tumour size Will be assessed at baseline and at 12 weeks.
    - AEs will be collected at every study visit
    - Blood sampling for PK analysis will be carried out at pre-defined time-points during Cycle 1.
    - PFS will be assessed at baseline and every 6 weeks from Day 1 of cycle 1.
    - Duration of response will be assessed at baseline and every 6 weeks from Day 1 of cycle 1.
    - OS will be assessed at every visit (on treatment) and every 3 months until all patients have died or have been followed up for at least 18 months after registration of the last patient on study, whichever is sooner.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    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) 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 No
    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.8.3 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 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 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 study' is defined as the date when all patients have died or have been followed up for at least 18 months after registration.
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    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: 118
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 0
    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 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 state118
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 0
    F.4.2.2In the whole clinical trial 118
    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 cannot continue on study medication after they come off study. Further treatment is at the doctor's discretion. No cross-over is planned for this study.
    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 Decision2015-04-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-04-27
    P. End of Trial
    P.End of Trial StatusOngoing
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