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    Summary
    EudraCT Number:2016-003904-29
    Sponsor's Protocol Code Number:RG_16-186
    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:2019-10-08
    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 number2016-003904-29
    A.3Full title of the trial
    International phase I/II expansion trial of the MEK inhibitor selumetinib in combination with dexamethasone for the treatment of relapsed/refractory RAS-pathway mutated paediatric and adult Acute Lymphoblastic Leukaemia
    Internationale fase I/II studie met MEK inhibitor selumetinib in combinatie met dexamethason voor de behandeling van gerecidiveerde/refractaire RAS gemuteerde acute lymfatische leukemie bij kinderen en volwassenen
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    SeluDex
    SeluDex
    A.3.2Name or abbreviated title of the trial where available
    SeluDex
    SeluDex
    A.4.1Sponsor's protocol code numberRG_16-186
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN92323261
    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 Birmingham
    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.4.1Name of organisation providing supportCancer Research UK
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Birmingham
    B.5.2Functional name of contact pointDeborah Bird
    B.5.3 Address:
    B.5.3.1Street AddressCancer Research UK Clinical Trials Unit, University of Birmingham
    B.5.3.2Town/ cityBirmingham
    B.5.3.3Post codeB15 2TT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01214146754
    B.5.5Fax number01214143529
    B.5.6E-mailseludex@trials.bham.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 nameSelumetinib
    D.3.2Product code AZD6244, ARRY 142886
    D.3.4Pharmaceutical form Capsule
    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 INNSelumetinib
    D.3.9.1CAS number 606143-52-6
    D.3.9.2Current sponsor codeAZD6244, ARRY 142886
    D.3.9.3Other descriptive nameSELUMETINIB
    D.3.9.4EV Substance CodeSUB32237
    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.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, ARRY 142886
    D.3.4Pharmaceutical form Capsule
    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 INNSelumetinib
    D.3.9.1CAS number 606143-52-6
    D.3.9.2Current sponsor codeAZD6244, ARRY 142886
    D.3.9.3Other descriptive nameSELUMETINIB
    D.3.9.4EV Substance CodeSUB32237
    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
    Relapsed/refractory acute lymphoblastic leukaemia with mutation in the RAS pathway
    E.1.1.1Medical condition in easily understood language
    Relapsed/refractory acute lymphoblastic leukaemia with mutation in the RAS pathway
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10000845
    E.1.2Term Acute lymphoblastic leukemia
    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 define the recommended phase II dose (RP2D) of selumetinib in combination with dexamethasone in adult and paediatric patients with relapsed/refractory, RAS pathway mutant ALL, and to assess the preliminary anti-leukaemic activity of the combination in those patients
    E.2.2Secondary objectives of the trial
    To evaluate the safety and tolerability of the combination of selumetinib and dexamethasone, and to evaluate selumetinib and N-desmethyl selumitinib pharmacokinetics when given in combination with dexamethasone.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Morphologically proven relapsed/refractory (M2 or M3 marrow; ≥1st relapse for adults, ≥2nd relapse in paediatric group) or progressive B cell precursor or T-Acute Lymphoblastic Leukaemia (ALL) with demonstrated RAS pathway activating mutations (NRAS, KRAS, FLT3, PTPN11, cCBL) identified during the trial screening process
    - Group P (paediatric): <18 years of age; Group A (adult): ≥18 years of age
    - Adequate renal function:
    o Group A: Serum creatinine <1.5 x upper limit of normal (ULN)
    o Group P as follows:
     ≤ 5 years: Serum creatinine <0.8 mg/dL or 70 μmol/L
     > 5 years but ≤ 10 years: Serum creatinine <1 mg/dL or 88 μmol/L
     > 10 years but ≤ 15 years: Serum creatinine <1.2 mg/dL or 106 μmol/L
     > 15 years: Serum creatinine <1.5 mg/dL or 132 μmol/L
    - Patient is able to swallow selumetinib capsules whole
    - Performance status (PS): Group A - Eastern Cooperative Oncology Group (ECOG) ≤2 (Appendix 6); Group P - Lansky play scale ≥60% (Appendix 7) or Karnofsky scale ≥60% (Appendix 8)
    - Female patients post menarche: negative pregnancy test
    - Sexually active participants must agree to use appropriate contraception whilst on trial
    - Written informed consent
    - Absence of any psychological, familial, sociological or geographical factors potentially hampering compliance with the trial protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
    -Patients who relapse or progress after HSCT need to be at least at day +100, with no signs of Graft versus Host Disease and off immunosuppressive therapy for at least one week.
    - Patients who relapse or progress after CAR T cell therapy should be at least 4 weeks after infusion of CAR T cells.
    - Patients must have a body surface area (BSA) ≥ 0.55 m2.
    E.4Principal exclusion criteria
    - ALL without presence of RAS-pathway activating mutations
    - Mature B-cell leukaemia and Philadelphia positive ALL
    - Prior exposure to MEK, RAS or RAF inhibitors
    - Any unresolved toxicity ≥ CTCAE Grade 2 from previous anti-cancer therapy, except for alopecia
    - Cardiac conditions as follows:
    - Group A and P
    o Prior or current cardiomyopathy including but not limited to the following:
    • Known hypertrophic cardiomyopathy
    • Known arrhythmogenic right ventricular cardiomyopathy
    o Even if full recovery has occurred, previous moderate or severe impairment of
    left ventricular systolic function (LVEF <45% on ECHO in Group A; SF <29% in Group P but excluding transient impairments due to e.g. anaemia/sepsis or
    results not thought to represent a true reflection of cardiac function)
    o Severe valvular heart disease
    o Severe congential heart disease
    o Uncontrolled hypertension:
     Group A: BP ≥150/95 mmHg despite medical therapy
     Group P: BP ≥95th percentile for age, height and gender (please refer
    to Blood Pressure by Age and Height Percentiles tables in Appendices
    9 and 10)
    -Group A
    o Baseline (LVEF) below the lower limit of normal (LLN) or <55% measured by ECHO
    o Acute coronary syndrome within 6 months prior to trial registration
    o Uncontrolled Angina - Canadian Cardiovascular Society grade II-IV despite
    medical therapy (Appendix 11)
    o Symptomatic heart failure New York Heart Association (NYHA) Class II-IV, prior or current cardiomyopathy, or severe valvular heart disease (Appendix 12)
    o Prior or current cardiomyopathy including but not limited to the following:
    • Known hypertrophic cardiomyopathy
    • Known arrhythmogenic right ventricular cardiomyopathy
    o Atrial fibrillation with a ventricular rate >100 bpm on Electrocardiogram (ECG) at rest
    o QTcF >450ms in male patients or ≥460ms in female patients, or other factors that increase the risk of QT prolongation
    -Group P
    o Baseline SF <29%
    o Atrial fibrillation with a ventricular rate >130 bpm on Electrocardiogram (ECG)
    at rest
    o QTcF >450ms in patients <12 years or ≥460ms in patients ≥12 but <18 years
    - Ophthalmological conditions as follows:
    o Current or past history of retinal pigment epithelial detachment (RPED)/central
    serous retinopathy (CSR) or retinal vein occlusion
    o Intraocular pressure (IOP) > 21 mmHg or uncontrolled glaucoma (irrespective of IOP)
    - Pregnant and breast feeding females
    - Known severe hypersensitivity to selumetinib, dexamethasone or combination medications or any excipient of these medicinal products, or history of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib
    - Have received or are receiving an IMP or other systemic anti-cancer treatment (not including dexamethasone or hydroxycarbamide) within 4 weeks (6 weeks for nitrosoureas, mitomycin, and suramin) prior to trial registration, or within a period during which the IMP or systemic anticancer treatment has not been cleared from the body (e.g. a period of 5 ‘half-lives’), whichever is the most appropriate and as judged by the investigator
    - Have had recent major surgery within a minimum 4 weeks prior to trial registration, with the exception of surgical placement of vascular access
    -Have received radiation therapy within 4 weeks prior to trial registration, or limited field of radiation for palliation within 7 days of the first dose of trial treatment
    - Laboratory values as listed below (SI units):
    o Serum bilirubin >1.5 x ULN (unless due to Gilbert’s syndrome
    - Have evidence of any other significant clinical disorder or laboratory finding that, as judged by the investigator, makes it undesirable for the patient to participate in the trial
    -Have any evidence of a severe or uncontrolled systemic disease (e.g. unstable or
    uncompensated respiratory, cardiac, hepatic, or renal disease, active infection
    (including hepatitis B, hepatitis C, HIV), active bleeding diatheses, or renal
    transplant)

    - Have refractory nausea and vomiting, chronic gastrointestinal diseases (e.g.,
    inflammatory bowel disease), or significant bowel resection that would adversely
    affect the absorption/bioavailability of the orally administered trial medication

    - Any other active malignancy which, in the opinion of the investigator would limit
    the ability of the patient to complete the study
    E.5 End points
    E.5.1Primary end point(s)
    Phase I - The occurrence/non-occurrence of dose limiting toxicities (DLTs) in the trial defined assessment period

    Phase II - Response to treatment at 28 days as measured by morphological response (complete remission (CR), complete remission with incomplete platelet recovery (CRi), partial remission (PR), Non-response (NR) (see Appendix 2 for Response Definitions)) and MRD response in BM and clearance of CSF blasts
    E.5.1.1Timepoint(s) of evaluation of this end point
    The analysis (for each group) for the dose decision phase of the trial will take place once 12 patients have been followed for the DLT assessment period, at this stage a decision will be made as to which dose to take forward to the phase II dose expansion element of the trial.

    The analysis for the primary outcome of the dose expansion phase (phase II) of the trial will take place once the final patient has been followed for 28 days for response assessment.
    E.5.2Secondary end point(s)
    Phase I
    - The occurrence of adverse events (AEs) as measured by Common Terminology
    Criteria for Adverse Events (CTCAE) version 4 and causality assessment
    - Pharmacokinetic variables of selumetinib in combination with dexamethasone from the concentration time profile (area under the curve (AUC), Cmax, Tmax, t1/2)
    - Response to treatment assessed by complete remission rate at 28 days (max 35 days) as measured by morphological and minimal residual disease (MRD) response in bone marrow (BM) and clearance of Cerebrospinal Fluid (CSF) blasts
    -Difference in pharmacokinetics of selumetinib (ΔAUC) when selumetinib is
    administered as single agent and in combination with dexamethasone

    Phase II
    - The occurrence of AEs as measured by CTCAE version 4 and causality assessment
    - The occurrence/non-occurrence of DLTs in the trial defined assessment period
    - Pharmacokinetic variables of selumetinib in combination with dexamethasone from the concentration time profile (AUC, Cmax, Tmax, t1/2)
    - Difference in pharmacokinetics of selumetinib (ΔAUC) when selumetinib is
    administered as single agent and in combination with dexamethasone
    E.5.2.1Timepoint(s) of evaluation of this end point
    The analysis (for each group) for the dose decision phase of the trial will take place once 12 patients have been followed for the DLT assessment period, at this stage a decision will be made as to which dose to take forward to the phase II dose expansion element of the trial.

    The analysis for the primary outcome of the dose expansion phase (phase II) of the trial will take place once the final patient has been followed for 28 days for response assessment.
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Dose finding and toxicity assessment
    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.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    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 the trial will be 6 months after last data capture. This will allow sufficient time for the completion of protocol procedures, data collection and data input. The applicable NCC will notify the relevant Competent Authority and REC that the trial has ended at the appropriate time and will provide them with a summary of the clinical trial report within 12 months of the end of trial.
    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 months3
    E.8.9.1In the Member State concerned days31
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days31
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 21
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 7
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 7
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 7
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 11
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Infants, Toddlers and Children
    Zuigelingen, peuters en kinderen
    F.3.3.7Others Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 42
    F.4.2.2In the whole clinical trial 42
    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 will continue on treatment for as long as they benefit and do not experience unacceptable toxicity (unless they choose to discontinue trial treatment) only for the duration of the trial (6 cycles, approximately 6 months). There will not be continued access following this. All side effects will be monitored until resolution. Patients may be offered alternative standard or trial treatment where applicable.
    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 Decision2019-10-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-05-13
    P. End of Trial
    P.End of Trial StatusOngoing
    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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