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    The EU Clinical Trials Register currently displays   43881   clinical trials with a EudraCT protocol, of which   7295   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2010-021531-13
    Sponsor's Protocol Code Number:UCL/10/0035
    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:2011-01-11
    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 number2010-021531-13
    A.3Full title of the trial
    Multi-centre, randomised, double-blind phase II study comparing cediranib (AZD2171) plus gefitinib (Iressa, ZD1839) with cediranib plus placebo in subjects with recurrent/progressive glioblastoma (DORIC Trial)
    A.3.2Name or abbreviated title of the trial where available
    Phase II trial of cediranib +/- gefitinib for recurrent glioblastoma
    A.4.1Sponsor's protocol code numberUCL/10/0035
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorJoint UCLH and UCL Biomedical Research Unit
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 nameCediranib
    D.3.2Product code AZD2171
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPGastroenteral use
    Oral use
    Nasogastric use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCediranib
    D.3.9.1CAS number 288383-20-0
    D.3.9.3Other descriptive name4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]quinazoline
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number15 to 30
    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) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Iressa
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    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 nameIressa
    D.3.2Product code ZD1839
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPGastroenteral use
    Oral use
    Nasogastric use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGefitinib
    D.3.9.1CAS number 184475-35-2
    D.3.9.3Other descriptive nameN-​(3-​chloro-​4-​fluorophenyl)-​7-​methoxy-​6-​[3-​(4-​morpholinyl)propoxy]-​4-​quinazolinamine
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 placeboFilm-coated tablet
    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
    Glioblastoma
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 13.1
    E.1.2Level PT
    E.1.2Classification code 10018336
    E.1.2Term Glioblastoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the efficacy of cediranib in combination with oral gefitinib with cediranib alone. The primary outcome variable will be progression free survival as defined as the date from randomisation to the date of first progression or death due to any cause, whichever one comes first.
    E.2.2Secondary objectives of the trial
    • To document the safety and tolerability of cediranib in combination with oral gefitinib and cediranib alone.
    • To compare cediranib in combination with oral gefitinib and cediranib alone in terms of steroid sparing effects
    • To document the quality of life and neurological symptoms reported by patients taking cediranib in combination with oral gefitinib and cediranib alone.
    • To investigate the relationship between the effects of cediranib (+/- gefitinib) on levels of soluble angiogenesis biomarkers and clinical efficacy
    • To investigate the relationship between the patient’s genetic profile and efficacy of cediranib (+/- gefitinib)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Provision of informed consent

    • Age ≥18 years

    • Life expectancy ≥ 12 weeks

    • Histological/cytological confirmation of glioblastoma (WHO grade IV)

    • Patients with measurable disease (contrast-enhancing tumour ≥10 mm by shortest diameter on 2 axial slices) by MRI imaging within 7 days prior to enrolment. (If patients have recently had a routine MRI scan, this should be assessed before deciding whether or not to screen the patient, and booking the screening/baseline MRI.)

    • Patients must have been on no steroids or a stable dose of steroids (dexamethasone) for at least 5 days before the baseline MRI

    • Patients must have completed standard first-line treatment for glioblastoma including surgery (with exception, if patient does not receive surgery as part of first-line treatment due to anatomical location, based on neurosurgeon’s assessment), cranial radiotherapy and chemotherapy with concomitant temozolomide. It is not essential that the entire Stupp regimen of 6 cycles of adjuvant temozolomide following chemoradiotherapy has been completed. The last dose of temozolomide must be more than 28 days from enrolment. Gliadel® wafers are permitted, as it is part of local treatment. No other previous treatment for glioblastoma is permitted (other than steroids).

    • Patients must have a Karnofsky Performance Score of 70 or above

    • Patients must have a mini-mental status examination score of 15 or greater

    • Patients who require either oral anticoagulants (coumadin, warfarin) or low molecular weight heparin are eligible provided there is increased vigilance with respect to monitoring INR.

    For inclusion in this genetic research, patients must fulfil the following criterion:

    • Provision of informed consent for genetic research (separate consent required for tumour biopsy, blood sample, and post mortem donations)
    E.4Principal exclusion criteria
    • Patients on enzyme-inducing anti-epileptic drugs within 2 weeks prior to study enrolment. Note: Patients are eligible if they switched to non-enzyme inducing agents and discontinued enzyme-inducing agents for more than or equal to 2 weeks prior to randomisation

    • Inadequate bone marrow reserve as demonstrated by an absolute neutrophil count ≤1.5 x 109 /L or platelet count ≤100 x 109 /L or requiring regular blood transfusions to maintain haemoglobin >9g/dL

    • Serum bilirubin ≥1.5 x ULRR (Upper Limit of the Reference Range)(except for patients with known documented cases of Gilbert’s Syndrome)

    • ALT or AST ≥5 x ULRR

    • Serum creatinine >1.5 x ULRR or a creatinine clearance of ≤50mL/min calculated by Cockcroft-Gault

    • Greater than +1 proteinuria on two consecutive dipsticks taken no less than 1 week apart unless urinary protein <1.5g in a 24 hr period or UPC (Urine Protein: Creatinine) ratio <1.5

    • History of significant gastrointestinal impairment, as judged by the investigator, that would significantly affect the absorption of cediranib or gefitinib, including the ability to swallow the tablet whole

    • Patients with a history of poorly controlled hypertension with resting blood pressure >150/100mmHg in the presence or absence of a stable regimen of anti-hypertensive therapy, or patients who are requiring maximal doses of calcium channel blockers to stabilise blood pressure

    • Any evidence of severe or uncontrolled diseases (e.g. unstable or uncompensated respiratory, cardiac, hepatic or renal disease)

    • Unresolved toxicity >CTC AE grade 1 from previous anti-cancer therapy (including radiotherapy) except alopecia (if applicable)

    • Mean QTc with Bazetts correction >470msec in screening ECG or history of familial, long QT syndrome

    • Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy

    • Significant haemorrhage (>30mL bleeding/episode in previous 3 months) or haemoptysis (>5mL fresh blood in previous 4 weeks)

    • Recent (<14 days) major surgery or brain biopsy. Recent craniotomy (<28 days) prior to first dose, or a surgical incision that is not fully healed

    • Pregnant or breast-feeding women or women of childbearing potential with a positive pregnancy test prior to receiving study medication

    • Known hypersensitivity to cediranib, gefitinib or any of its excipients

    • History of other malignancies (except for adequately treated basal or squamous cell carcinoma or carcinoma in situ) within 5 years, unless the patient has been disease free for 2 years and they have tissue diagnosis of the target lesion

    • Known infection with hepatitis B or C or HIV

    • Involvement in the planning and conduct of the study (applies to both UCL CTC, AstraZeneca staff and staff at the study site)

    • Past medical history of interstitial lung disease, idiopathic pulmonary fibrosis, drug-induced interstitial disease, radiation pneumonitis which required steroid treatment or any evidence of clinically active interstitial lung disease

    • Previous enrolment as part of the present study

    • Treatment with an investigational drug within 30 days prior to the first dose of cediranib/gefitinib

    • Other concomitant anti-cancer therapy except steroids (dexamethasone only)

    • Previous anti-angiogenesis (e.g. bevacizumab, sorafenib, sunitinib) therapy

    • Previous anti-EGFR treatments (e.g. cetuximab, panitumumab or small molecule tyrosine kinase inhibitors etc.) or downstream targets mTOR inhibitors.

    • Patients with evidence of any intratumoural or peritumoural haemorrhage deemed significant by the treating physician

    • Patients who have received any form of cranial radiation within 3 months prior to study entry (excluding imaging)

    • Patients who have progressed within 3 months of completion of standard cranial radiation

    • Patients that have received radiosurgery or brachytherapy

    • Patients on >8mg/day dexamethasone or equivalent steroids on any day of the 2 weeks prior to randomisation
    E.5 End points
    E.5.1Primary end point(s)
    Progression free survival (PFS) defined as the time from the date of randomisation to the date of first progression or death due to any cause, whichever one comes first.

    Progression will be determined using site determination of performance status and a central review of the MRI scans, and by working to a modified version of the RANO criteria (Response Assessment in Neuro-oncology), see Wen et al 2010, as described in the protocol.

    Wen PY, Macdonald DR, Reardon DA et al. Updated response criteria for highgrade
    gliomas: response assessment in neurooncology working group. J Clinical Oncology 2010: 28: 19631972
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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 Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    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 Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.3 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.8.6 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 Information not present in EudraCT
    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
    For regulatory purposes the end of the trial will be 6 months from the date the last patient finished trial treatment or the date the last patient dies, whichever is sooner. At this point it is judged that all relevant safety data and primary endpoint data will have been catured. Long term follow up will be continued until the last patient has died in order to capture all secondary endpoint data.
    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 months6
    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 months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women Information not present in EudraCT
    F.3.3.4Nursing women Information not present in EudraCT
    F.3.3.5Emergency situation Information not present in EudraCT
    F.3.3.6Subjects incapable of giving consent personally Information not present in EudraCT
    F.3.3.7Others Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state112
    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)
    Cediranib and gefitinib will be available for patients until unblinding, discontinuation or voluntary withdrawal from the trial. Patients will be allowed to take 14 day drug-holidays (21 days in consultation with the chief investigator) and then restart the trial drug as part of the trial. It is explained in the patient information sheet that "Once you have come off the study you will no longer be able to take trial medication". The research will continue until patient death therefore there will
    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 Decision2011-02-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-02-17
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-01-23
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