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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2016-003904-29
    Trial protocol
    		 GB   NL   FR   DK  
    Global end of trial date
    26 Aug 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Apr 2025
    First version publication date
    20 Apr 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RG_16-186
    Additional study identifiers
    ISRCTN number
    		 ISRCTN92323261
    US NCT number
    		 NCT03705507
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Birmingham
    Sponsor organisation address
    Edgbaston, Birmingham, United Kingdom, B15 2TT
    Public contact
    Joshua Savage, University of Birmingham, seludex@trials.bham.ac.uk
    Scientific contact
    Joshua Savage, University of Birmingham, seludex@trials.bham.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Dec 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jul 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Aug 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main 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-leukemic activity of the combination in those patients.
    Protection of trial subjects
    Trial Safety Commitee (TSC) was established to provide independent oversight of the trial and provide advice through its independent chair. The TSC will include a patient representative and a sponsor’s representative. The Chief Investigator will report to the committee on behalf of the TMG. The TSC will assume responsibility for the oversight of the trial on behalf of the Coordinating Sponsor. The TSC will meet or hold teleconferences at least once a year, or more often if required. The TSC will take on the responsibilities similar to that of a data monitoring committee on late phase trials. Established by the Sponsor, the TSC will assess at intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, including dose decisions, and to recommend to the Sponsor whether to continue, modify, or stop a trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Apr 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    United Kingdom: 10
    Worldwide total number of subjects
    12
    EEA total number of subjects
    2
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    3
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    4
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial opened to recruitment on 17th April 2018 with the first patient recruited on 18th May 2018. The last patient was recruited on 10th August 2021 and the trial closed to recruitment on 3rd May 2023. Patients were recruited from sites across the UK, and one site in the Netherlands. Sites also opened in France & Denmark but did not recruit.

    Pre-assignment
    Screening details
    		 RAS pathway activating mutations (NRAS, KRAS, FLT3, PTPN11, cCBL, NF1, BRAF, IKZF2, IKZF3, IL7Rα or JAK1) were identified during the trial screening process with local analysis or central analysis by Northern Genetics Service.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A
    Arm description
    		 Group A enrolled patients who are 18 years or older
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selumetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    All patients entered onto the dose finding element of the trial will receive treatment as per protocol. Starting dose (dose level 0) 75mg BD PO. Cycle 1 D1: single dose, Cycle 1 D4-D28: BD dosing, Subsequent cycles 2-6: D1-28: BD dosing.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cycle 1 D2-4 & D8-11: 6mg/m2/day, D15-18 & D22-25: 4mg/m2/day. Cycle 2 D1-4: 4mg/m2/day Subsequent cycles 3-6, D1-5 only 6mg/m2/day

    Arm title
    		 Group P
    Arm description
    		 Group P enrolled patients under 18 years of age
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selumetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    All patients entered onto the dose finding element of the trial will receive treatment as per protocol. Starting dose (dose level -1) 20mg/m2 BD PO. Cycle 1 D1 single dose, Cycle 1 D4-D28: BD dosing, Subsequent cycles 2-6: D1-28: BD dosing.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cycle 1 D2-4 & D8-11: 6mg/m2/day, D15-18 & D22-25: 4mg/m2/day. Cycle 2 D1-4: 4mg/m2/day Subsequent cycles 3-6, D1-5 only 6mg/m2/day

    Number of subjects in period 1
    		Group A Group P
    Started
    8
    4
    Completed
    7
    4
    Not completed
    1
    0
         Died before starting trial treatment
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 12 12
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 3 3
        Adolescents (12-17 years)
    		 1 1
        Adults (18-64 years)
    		 4 4
        From 65-84 years
    		 4 4
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 25 (5 to 73) -
    Gender categorical
    Units: Subjects
        Female
    		 2 2
        Male
    		 10 10
    Ethnicity
    Units: Subjects
        Any other Asian background
    		 1 1
        Any other ethnic group
    		 1 1
        Arab
    		 1 1
        Bangladeshi
    		 1 1
        Caribbean
    		 1 1
        English/Welsh/Scottish/Northern Irish/British
    		 7 7
    Current ALL disease status
    Units: Subjects
        Progressive
    		 1 1
        Refractory
    		 2 2
        Relapsed
    		 9 9
    CNS disease status at diagnosis
    Units: Subjects
        CNS1
    		 7 7
        CNS2
    		 1 1
        CNS3
    		 1 1
        Unknown
    		 3 3
    Previously received CAR T cell therapy
    Units: Subjects
        No
    		 9 9
        Yes
    		 3 3
    Previously received HSCT
    Units: Subjects
        No
    		 7 7
        Yes
    		 5 5
    ALL classification
    Units: Subjects
        B-cell precursor ALL
    		 6 6
        T-ALL
    		 6 6
    ECOG Performance Status
    Units: Subjects
        PS0
    		 1 1
        PS1
    		 4 4
        PS2
    		 1 1
        Unknown
    		 6 6
    Bone marrow blast score
    Units: Subjects
        M2
    		 2 2
        M3
    		 9 9
        Unknown
    		 1 1
    Cellularity
    Units: Subjects
        Hypercellular
    		 5 5
        Hypocellular
    		 2 2
        Normocellular
    		 3 3
        Unknown
    		 2 2
    CNS disease classification in CSF
    Units: Subjects
        CNS1
    		 10 10
        CNS3
    		 1 1
        Unknown
    		 1 1
    Weight
    Units: kilogram(s)
        median (full range (min-max))
    		 67 (27 to 128) -
    Height
    Units: metre
        median (full range (min-max))
    		 1.71 (1.17 to 1.89) -
    Body Surface Area
    Units: m2
        median (full range (min-max))
    		 1.79 (0.96 to 2.60) -

    End points

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    End points reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Group A enrolled patients who are 18 years or older

    Reporting group title
    Group P
    Reporting group description
    		 Group P enrolled patients under 18 years of age

    Primary: Dose Limiting Toxicities

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    End point title
    		 Dose Limiting Toxicities [1]
    End point description
    The occurrence/non-occurrence of dose limiting toxicities (DLTs) in the trial defined assessment period. A DLT is defined as any toxicity which is dose limiting, is not attributable to the disease or disease-related processes under investigation, and is considered at least possibly related to either of the investigational medicinal products (IMPs), as defined in the protocol.
    End point type
    Primary
    End point timeframe
    DLTs will be assessed from the first dose on Cycle 1 Day 1 up until Cycle 1 Day 28 during Phase I only.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Primary Objective to define the recommended phase II dose (RP2D) of selumetinib/dexamethasone combination in adult and paediatric patients with relapsed/refractory RAS pathway mutant ALL. Modified 2-stage Bayesian Continual Reassessment Method (CRM) was used to determine the maximum tolerated dose independently for each patient group based on the occurrence/non-occurrence of DLT. Dose decision was then made by the Trial Safety Committee. The CRM Dose Decision endpoint is the statistical analysis
    End point values
    		 Group A Group P
    Number of subjects analysed
    7
    4
    Units: Events
    1
    1
    No statistical analyses for this end point

    Primary: CRM Dose Decision

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    End point title
    		 CRM Dose Decision [2]
    End point description
    The trial target rate of DLT is 0.17 (17%). For Group A: Dose level 0 has the closest posterior probability estimate (0.154) to this target rate of 0.17. Therefore, the modified Continual Reassessment Method (CRM) recommended dose level 0 for future adult patients (Group A). For Group P: Dose level -1 has the closest posterior probability estimate (0.207) to this target rate of 0.17. Therefore, the modified Continual Reassessment Method (CRM) recommended dose level -1 for future paediatric patients (Group P).
    End point type
    Primary
    End point timeframe
    DLTs will be assessed from the first dose on Cycle 1 Day 1 up until Cycle 1 Day 28 during Phase I only.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Primary Objective to define the recommended phase II dose (RP2D) of selumetinib/dexamethasone combination in adult & paediatric patients with relapsed/refractory RAS pathway mutant ALL. Modified 2-stage Bayesian Continual Reassessment Method (CRM) was used to determine the maximum tolerated dose independently for each patient group based on occurrence/non-occurrence of DLT. Dose decision was then made by Trial Safety Committee. This result of posterior probability is the statistical analysis.
    End point values
    		 Group A Group P
    Number of subjects analysed
    7
    4
    Units: Posterior Probability
        number (confidence interval 95%)
    0.154 (0.02 to 0.41)
    0.207 (0.022 to 0.52)
    No statistical analyses for this end point

    Secondary: Response

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    End point title
    		 Response
    End point description
    Response to treatment assessed by complete remission rate at 28 days as measured by morphological and minimal residual disease (MRD) response in bone marrow (BM) and for patients with CNS involvement only clearance of Cerebrospinal Fluid (CSF) blasts at 28 days
    End point type
    Secondary
    End point timeframe
    Response at Cycle 1 Day 28
    End point values
    		 Group A Group P
    Number of subjects analysed
    6
    3
    Units: Patients
        CR: Complete Remission
    1
    1
        CRi: Complete remission incomplete platelet recov.
    2
    0
        PR: Partial remission
    0
    0
        NR: No response
    3
    2
    No statistical analyses for this end point

    Secondary: Pharmacokinetics - AUC

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    End point title
    		 Pharmacokinetics - AUC
    End point description
    PK of Selumetinib in combination with dexamethasone
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 4 and Cycle 2 Day 1
    End point values
    		 Group A Group P
    Number of subjects analysed
    7 [3]
    4 [4]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 4
    4418 ( 936 )
    1407 ( 1158 )
        Cycle 2 Day 1
    4872 ( 2447 )
    1649 ( 1058 )
    Notes
    [3] - Cycle 2 Day 1 subjects: 5
    [4] - Cycle 2 Day 1 subjects: 3
    No statistical analyses for this end point

    Secondary: Pharmacokinetics - CMax

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    End point title
    		 Pharmacokinetics - CMax
    End point description
    PK of Selumetinib in combination with dexamethasone
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 4 and Cycle 2 Day 1
    End point values
    		 Group A Group P
    Number of subjects analysed
    7 [5]
    4 [6]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 4
    1512 ( 577 )
    474 ( 335 )
        Cycle 2 Day 1
    1097 ( 442 )
    515 ( 341 )
    Notes
    [5] - Cycle 2 Day 1 subjects: 5
    [6] - Cycle 2 Day 1 subjects: 3
    No statistical analyses for this end point

    Secondary: Pharmacokinetics - TMax

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    End point title
    		 Pharmacokinetics - TMax
    End point description
    PK of Selumetinib in combination with dexamethasone
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 4 and Cycle 2 Day 1
    End point values
    		 Group A Group P
    Number of subjects analysed
    7 [7]
    4 [8]
    Units: h
    arithmetic mean (standard deviation)
        Cycle 1 Day 4
    1.11 ( 0.31 )
    1.95 ( 0.07 )
        Cycle 2 Day 1
    1.80 ( 1.30 )
    1.60 ( 0.61 )
    Notes
    [7] - Cycle 2 Day 1 subjects: 5
    [8] - Cycle 2 Day 1 subjects: 3
    No statistical analyses for this end point

    Secondary: Pharmacokinetics - THalf

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    End point title
    		 Pharmacokinetics - THalf
    End point description
    PK of Selumetinib in combination with dexamethasone
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 4 and Cycle 2 Day 1
    End point values
    		 Group A Group P
    Number of subjects analysed
    7 [9]
    4 [10]
    Units: h
    arithmetic mean (standard deviation)
        Cycle 1 Day 4
    1.85 ( 0.31 )
    1.30 ( 0.14 )
        Cycle 2 Day 1
    2.50 ( 0.70 )
    2.37 ( 0.87 )
    Notes
    [9] - Cycle 2 Day 1 subjects: 5
    [10] - Cycle 2 Day 1 subjects: 3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All medical occurrences which meet the definition of an AE should be reported from the date of commencement of protocol defined treatment until 28 days after the administration of the last treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Group A enrolled patients who are 18 years or older

    Reporting group title
    Group P
    Reporting group description
    		 Group P enrolled patients under 18 years of age

    Serious adverse events
    		 Group A Group P
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 7 (85.71%)
    3 / 4 (75.00%)
         number of deaths (all causes)
    7
    4
         number of deaths resulting from adverse events
    4
    1
    Cardiac disorders
    Heart failure
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Catheter related infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations - Other: Buttock Abscess
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations - Other: Neutropenic sepsis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations - Other: Right sided pneumonia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 4 (50.00%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    1 / 2
    1 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Group A Group P
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    4 / 4 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Hypotension
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    3
    Vascular access complication
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Edema face
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Edema limbs
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 4 (0.00%)
         occurrences all number
    7
    0
    Fatigue
         subjects affected / exposed
    4 / 7 (57.14%)
    0 / 4 (0.00%)
         occurrences all number
    15
    0
    Fever
         subjects affected / exposed
    3 / 7 (42.86%)
    2 / 4 (50.00%)
         occurrences all number
    10
    6
    Irritability
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    5
    0
    Dyspnea
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    Epistaxis
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    2
    Oesophagitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Right sided pneumonia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Euphoria
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Low mood
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 4 (25.00%)
         occurrences all number
    8
    16
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
         occurrences all number
    1
    11
    Blood bilirubin increased
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 4 (50.00%)
         occurrences all number
    1
    8
    Electrolyte disturbance
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    GGT increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    6
    0
    Ldh increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    13
    Neutrophil count decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
         occurrences all number
    4
    10
    Platelet count decreased
         subjects affected / exposed
    3 / 7 (42.86%)
    2 / 4 (50.00%)
         occurrences all number
    18
    11
    Weight gain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    White blood cell decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
         occurrences all number
    5
    10
    White cell count increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    Bruising
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    5
    Cardiac disorders
    Heart failure
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Pericardial effusion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Sinus bradycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Sinus tachycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    Hydrocephalus
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Lethargy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    15
    0
    Proximal myopathy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Tremor
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    ALT increase
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    Anemia
         subjects affected / exposed
    4 / 7 (57.14%)
    3 / 4 (75.00%)
         occurrences all number
    28
    14
    Cytopenia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Deranged clotting
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    Febrile neutropenia
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 4 (50.00%)
         occurrences all number
    5
    12
    Ggt
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    Papilledema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 4 (50.00%)
         occurrences all number
    2
    3
    Anal pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    6
    0
    Bloating
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
         occurrences all number
    12
    1
    Diarrhea
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 4 (50.00%)
         occurrences all number
    5
    3
    Dyspepsia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    3
    Esophagitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Hard stool
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Increased appetite
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Malabsorption
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    10
    Mucositis oral
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    9
    Nausea
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
         occurrences all number
    1
    2
    Stomach pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    3 / 7 (42.86%)
    1 / 4 (25.00%)
         occurrences all number
    3
    2
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Liver dysfunction
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    Alopecia
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 4 (0.00%)
         occurrences all number
    6
    0
    Buccal mucosa erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Dry ski
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Face and neck red
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Folliculitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    Petechial rash
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Pressure sore
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Rash maculo-papular
         subjects affected / exposed
    3 / 7 (42.86%)
    1 / 4 (25.00%)
         occurrences all number
    10
    1
    Renal and urinary disorders
    Jaundice
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Proteinuria
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    1
    Renal dysfunction
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    Urinary tract pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    11
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Bone pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    Generalized muscle weakness
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Mild cramps in hand
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Muscle weakness lower limb
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    11
    0
    Myalgia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Proximal myopathy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    5
    0
    Shoulder pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Bacteremia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Buttock abscess
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    6
    0
    Catheter related infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Lung infection
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Mouth ulcer
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Mouth ulcers - possible viral
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Mucosal infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Oral infection: candidiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Oropharyngeal candidiasis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Papulopustular rash
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Paronychia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    6
    0
    Sepsis
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 4 (50.00%)
         occurrences all number
    1
    3
    Sepsis due to relapsed all
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    7
    0
    Metabolism and nutrition disorders
    Hyperglycemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
         occurrences all number
    19
    0
    Hypoalbuminemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    6
    Hypokalemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    7
    Hypomagnesemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    7
    Hyponatremia
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 4 (25.00%)
         occurrences all number
    14
    2
    Hypophosphatemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    10
    Reduced oral intake
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jul 2017
    SA01: Protocol version 2.0 Submission to ethics committee to address changes made for the initial competent authority approval. Clairification of DLTs, contraception/pregnancy and associated eligibility criteria, dose rationale, risk mitigation startegy for AEs identified in Selumetinib IB.
    25 Oct 2017
    SA02: Protocol version 3.0 Various minor changes and corrections throughout protocol including changes and clarifications to schedule of events, eligibility criteria, outcome measures and IMP details.
    26 Jan 2018
    SA03: Protocol version 4.0 Change of Chief Investigator, coinvestigators, and trial management staff and updated contact details.
    14 Dec 2018
    SA07: Protocol version 5.0 Urgent Safety Measure to reduce dexamethasone dose in cycle 1 for Group A.
    01 May 2019
    SA10: Protocol version 6.0 Urgent Safety Measure to reduce dexamethasone dose in cycle 1 for Group P and mandate fluoroquinolone prophylaxis during cycle 1 for all patients.
    09 Sep 2019
    SA11: Protocol version 7.0 Urgent Safety Measure to amend dexamethasone dosing schedule from continuous to pulsed in cycle 1, to mandate fluoroquinolone prophylaxis during cycle 1 and 2 and to mandate co-trimoxazole prophylaxis during the trial for all patients.
    29 Nov 2019
    SA13: Protocol version 8.0 Changes and clarifications to schedule of events and sampling. Addition of possibility of continued access beyond 6 cycles of treatment. Other minor corrections/amendments.
    22 Mar 2020
    SA15: Protocol version 9.0 Clarification of screening process for central RAS mutation testing and Trial Office approved local testing throughout, and Inclusion of additional RAS-pathway activating mutations (NF1, BRAF, IKZF2, IKZF3, IL7Rα or JAK1) tested for locally that can be used for eligibility. Other minor corrections/amendments.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Trial terminated early from poor recruitment, due to a change in the standard of care for this patient population with the use of CAR-T cells.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/35246426
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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