Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   41449   clinical trials with a EudraCT protocol, of which   6807   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).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Single-Arm, Open-Label, Multi-Centre, Phase I/II Study Evaluating the Safety and Clinical Activity Of AUTO3, a CAR T Cell Treatment Targeting CD19 And CD22 in Paediatric And Young Adult Patients With Relapsed or Refractory B Cell Acute Lymphoblastic Leukaemia

    Summary
    EudraCT number
    2016-004680-39
    Trial protocol
    GB  
    Global end of trial date
    18 May 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Dec 2020
    First version publication date
    04 Dec 2020
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    AUTO3-PA1
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03289455
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Autolus Ltd
    Sponsor organisation address
    58 Wood Lane, White City, London, United Kingdom, W12 7RZ
    Public contact
    Clinical Project Manager, Autolus Ltd, +44 1483 920748, clinicaltrials@autolus.com
    Scientific contact
    Clinical Project Manager, Autolus Ltd, +44 1483 920748, clinicaltrials@autolus.com
    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
    18 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 May 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    18 May 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objectives of Phase 1 of this trial were to assess the overall safety and tolerability of AUTO3 administration and to confirm and evaluate the recommended Phase II dose (RP2D) and dosing schedule, and confirm maximum tolerated dose (MTD), if an MTD exists, of AUTO3 in both paediatric and adult patients. The main objective of Phase 2 of this trial was to evaluate the anti-leukaemic effect of AUTO3 in paediatric and young adult patients (aged 1-24 years).
    Protection of trial subjects
    This study was conducted in accordance with standards of Good Clinical Practice (as defined by the International Council on Harmonisation), ethical principles that have their origin in the Declaration of Helsinki and all applicable national and local regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Jul 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    24 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    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)
    17
    Adolescents (12-17 years)
    6
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Subjects were recruited at three study centres in the United Kingdom.

    Pre-assignment
    Screening details
    Screening procedures were performed up to 12 weeks before study drug was administered. After screening subjects went through the sequential stages of leukapheresis, and pre conditioning before subjects were treated with actual doses of 0.3 to 5.0 x 10^6 /kg CD19/CD22 CAR-positive T cells.

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

    Arms
    Arm title
    AUTO3
    Arm description
    Paediatric subjects with relapse or refractory B-cell acute lymphoblastic leukaemia (ALL).
    Arm type
    Experimental

    Investigational medicinal product name
    AUTO3 (CD19/22 CAR T cells)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Following preconditioning with chemotherapy (cyclophosphamide and fludarabine) subjects were treated with actual doses of 0.3 to 5.0 x 10^6 /kg CD19/CD22 Chimeric Antigen Receptor (CAR) positive T cells

    Number of subjects in period 1
    AUTO3
    Started
    23
    Leukapheresed
    20
    Started Preconditioning Therapy
    15
    Received Study Treatment
    15
    Completed
    0
    Not completed
    23
         Death
    1
         Not infused with AUTO3
    8
         Other
    2
         Progressive Disease
    12

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    -

    Reporting group values
    Overall Study Total
    Number of subjects
    23 23
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    9.0 ± 4.38 -
    Gender categorical
    Units: Subjects
        Female
    8 8
        Male
    15 15
    Race
    Units: Subjects
        Asian
    4 4
        White
    19 19
    Karnofsky/Lansky score
    Units: Percentage
        median (full range (min-max))
    90 (70 to 100) -
    Subject analysis sets

    Subject analysis set title
    Received Study Treatment
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set)

    Subject analysis sets values
    Received Study Treatment
    Number of subjects
    15
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    9.6 ± 4.36
    Gender categorical
    Units: Subjects
        Female
    4
        Male
    11
    Race
    Units: Subjects
        Asian
    1
        White
    14
    Karnofsky/Lansky score
    Units: Percentage
        median (full range (min-max))
    90 (80 to 100)

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    AUTO3
    Reporting group description
    Paediatric subjects with relapse or refractory B-cell acute lymphoblastic leukaemia (ALL).

    Subject analysis set title
    Received Study Treatment
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set)

    Primary: Incidence of Grade 3-5 Toxicities Occurring Within the Dose Limiting Toxicity (DLT) Period of AUTO3 Infusion

    Close Top of page
    End point title
    Incidence of Grade 3-5 Toxicities Occurring Within the Dose Limiting Toxicity (DLT) Period of AUTO3 Infusion [1]
    End point description
    End point type
    Primary
    End point timeframe
    Within 30 days (+/- 3 days) after the last dose of AUTO3
    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: Only summary statistics were planned for this endpoint.
    End point values
    AUTO3
    Number of subjects analysed
    15
    Units: Subjects
    14
    No statistical analyses for this end point

    Primary: Frequency of Dose Limiting Toxicity (DLT) of AUTO3

    Close Top of page
    End point title
    Frequency of Dose Limiting Toxicity (DLT) of AUTO3 [2]
    End point description
    DLT was defined as i) any new non-hematological AE of Grade 3 or higher toxicity using the NCI CTCAE (version 5.0), which is probably or definitely related to AUTO3 therapy, which occurs within the DLT evaluation period, and which fails to resolve to Grade 2 or better within 14 days, despite appropriate supportive measures; ii) Grade 4 CRS or neurotoxicity, cerebral edema, or Grade 3 neurotoxicity (including cerebral edema) that lasts >72 hours; iii) Grade >3 disseminated intravascular coagulation; iv) Grade >2 infusion reaction; v) Any other fatal event (Grade 5) or life-threatening event (Grade 4) that cannot be managed with conventional supportive measures or which in the opinion of the SEC necessitates dose reduction or other modification to trial treatment to avoid a similar hazard in future subjects.
    End point type
    Primary
    End point timeframe
    Within 30 days (+/- 3 days) after the last dose of AUTO3
    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: Only summary statistics were planned for this endpoint.
    End point values
    AUTO3
    Number of subjects analysed
    15
    Units: Subjects
    0
    No statistical analyses for this end point

    Primary: Proportion of Patients Achieving Morphological Remission (Complete Response(CR) or Complete Response With Incomplete Count Recovery (CRi) and Minimal Residual Disease (MRD)-Negative Response in the Bone Marrow (PCR)).

    Close Top of page
    End point title
    Proportion of Patients Achieving Morphological Remission (Complete Response(CR) or Complete Response With Incomplete Count Recovery (CRi) and Minimal Residual Disease (MRD)-Negative Response in the Bone Marrow (PCR)). [3]
    End point description
    End point type
    Primary
    End point timeframe
    Within 30 days (+/- 3 days) post AUTO3 infusion
    Notes
    [3] - 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: Only summary statistics were planned for this endpoint.
    End point values
    AUTO3
    Number of subjects analysed
    15
    Units: Subjects
    13
    No statistical analyses for this end point

    Secondary: Feasibility of Generating AUTO3: Number of Subjects' Cells Successfully Manufactured as a Proportion of the Number of Subjects Undergoing Leukapheresis

    Close Top of page
    End point title
    Feasibility of Generating AUTO3: Number of Subjects' Cells Successfully Manufactured as a Proportion of the Number of Subjects Undergoing Leukapheresis
    End point description
    Feasibility of product generation was examined by assessing the number of AUTO3 successfully manufactured as a fraction of the number of subjects undergoing leukapheresis (all subjects screened).
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks post leukapheresis
    End point values
    AUTO3
    Number of subjects analysed
    20 [4]
    Units: Subjects
    19
    Notes
    [4] - This endpoint includes all patients who were screened and underwent leukapheresis.
    No statistical analyses for this end point

    Secondary: Event-Free Survival (EFS) by Morphological Analysis

    Close Top of page
    End point title
    Event-Free Survival (EFS) by Morphological Analysis
    End point description
    Time from date of first AUTO3 infusion until the earliest of treatment failure (defined as not achieving CR/CRi post AUTO3 infusion / no response), morphological relapse, or death due to any cause, whichever occurred first.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    AUTO3
    Number of subjects analysed
    15
    Units: Months
        median (confidence interval 95%)
    4.90 (1.64 to 12.42)
    No statistical analyses for this end point

    Secondary: Incidence of CD19- and/or CD22-negative Relapse

    Close Top of page
    End point title
    Incidence of CD19- and/or CD22-negative Relapse
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    AUTO3
    Number of subjects analysed
    9
    Units: Subjects
    3
    No statistical analyses for this end point

    Secondary: Relapse-Free Survival (RFS) by Morphological Anlaysis

    Close Top of page
    End point title
    Relapse-Free Survival (RFS) by Morphological Anlaysis
    End point description
    Time from first achievement of morphological CR/CRi post AUTO3 treatment until the earliest of morphological relapse, or death due to any cause, whichever occurred first. 99999 is used as the upper limit of the confidence interval was not reached.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    AUTO3
    Number of subjects analysed
    15
    Units: Months
        median (confidence interval 95%)
    9.53 (1.87 to 99999)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

    Close Top of page
    End point title
    Overall Survival (OS)
    End point description
    Calculated from the date of AUTO3 treatment to the date of death anytime post AUTO3 infusion. Patients who had not died were censored at the date of last contact. 99999 is used where the upper limit of the confidence interval had not been reached.
    End point type
    Secondary
    End point timeframe
    Up to last patient last visit
    End point values
    AUTO3
    Number of subjects analysed
    15
    Units: Months
        median (confidence interval 95%)
    14.55 (4.34 to 99999)
    No statistical analyses for this end point

    Secondary: Expansion of AUTO3 Following Adoptive Transfer

    Close Top of page
    End point title
    Expansion of AUTO3 Following Adoptive Transfer
    End point description
    Expansion of AUTO3 was measured as the median peak (Cmax) of transgene levels in the peripheral blood after AUTO3 infusion.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    AUTO3
    Number of subjects analysed
    13
    Units: Vector copies/ug DNA
        median (full range (min-max))
    56100 (5690 to 127000)
    No statistical analyses for this end point

    Secondary: Persistence of AUTO3 Following Adoptive Transfer

    Close Top of page
    End point title
    Persistence of AUTO3 Following Adoptive Transfer
    End point description
    Persistence of AUTO3 was measured by qualitative polymerase chain reaction (PCR) and/or flow cytometry at a range of time points in the peripheral blood and the bone marrow. Persistence was defined as the timepoint in days of last detectable CAR T cell by qPCR or last assessment if zero copies per μg DNA (whichever occurred later) before morphological relapse (Tlast).
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    AUTO3
    Number of subjects analysed
    13
    Units: Days
        median (full range (min-max))
    62.7 (18.8 to 570.8)
    No statistical analyses for this end point

    Secondary: Duration of B Cell Aplasia

    Close Top of page
    End point title
    Duration of B Cell Aplasia
    End point description
    Depletion of circulating B cells assessed by flow cytometry at a range of time points in the peripheral blood. 99999 is entered as B cell aplasia from the database was inconclusive because the total lymphocytes from the peripheral blood analyzed by flow cytometry were not collected systematically.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    AUTO3
    Number of subjects analysed
    15
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From AUTO3 infusion (Day 0) to until the end of study or withdrawal, whichever occurred first.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    AUTO3
    Reporting group description
    Paediatric subjects with relapse or refractory B-cell acute lymphoblastic leukaemia (ALL).

    Serious adverse events
    AUTO3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 15 (40.00%)
         number of deaths (all causes)
    9
         number of deaths resulting from adverse events
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    AUTO3
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 15 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hypotension
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Fatigue
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    9 / 15 (60.00%)
         occurrences all number
    31
    Psychiatric disorders
    Hallucination
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Limb injury
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Procedural pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Soft tissue injury
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Human herpes virus 6 serology positive
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hypokalaemia
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    3
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    4
    Neutrophil count decreased
         subjects affected / exposed
    5 / 15 (33.33%)
         occurrences all number
    28
    Platelet count decreased
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    6
    Staphylococcus test positive
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hypoxia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Painful respiration
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pleural effusion
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    6
    Febrile neutropenia
         subjects affected / exposed
    6 / 15 (40.00%)
         occurrences all number
    6
    Neutropenia
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    8
    Thrombocytopenia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Headache
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    4
    Paraesthesia
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Syncope
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Eye disorders
    Vision blurred
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    3
    Abdominal pain upper
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    5
    Anal haemorrhage
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Lip dry
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Haematochezia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    5 / 15 (33.33%)
         occurrences all number
    5
    Stomatitis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Rash erythematous
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Rash maculo-papular
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Rash papular
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Aphasia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Neck pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    5 / 15 (33.33%)
         occurrences all number
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 15 (33.33%)
         occurrences all number
    6
    Gout
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hypophosphataemia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Infections and infestations
    Catheter bacteraemia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Enterococcal infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Device related infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Folliculitis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Gingival abscess
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Infectious pleural effusion
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Parvovirus infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Staphylococcal infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jun 2017
    Protocol version 2 - Summary of Changes: - Typographical and administrative changes - Changed dose escalation to dose evaluation/escalation - Expanded inclusion criterion 1c with broader definitions extreme hyperdiploidy or hypodiploidy - Added further clarity for high-risk CNS relapse subjects in inclusion criterion 1i and exclusion criterion 1 - Clarified screening window i.e. Day -84 to Day -35 - Clarified the inpatient period in the case of a split dose i.e. 30 (-3/+5) days post-AUTO3 infusion and up to 14 days after the second split dose - Added text to clarify when the second split dose can be administered i.e. only at ≤ Grade 1 CRS and no ongoing CRS or neurotoxicity at Day 7 - Clarified the procedure for re-starting the trial following a halt as per the safety stopping criteria - Clarified DLT period of 30 days (±3 days) after last dose or until start of a new ALL therapy - Added hypoxia risks and mitigation strategy, respiratory toxicity guidelines - Added GVHD risks and mitigation strategy as per the Investigator’s Brochure - Clarified early use of tocilizumab for CRS safety management - Added text to note patients will be monitored for CMV weekly during admission or as necessary - Updated frequency of IDMC meetings to every 6 months in Phase II. Added text regarding the information received and the decision(s) that can be taken by the IDMC, particularly with regards to opening Phase II - Updated the withdrawal of consent for patient samples stored for research
    24 Oct 2017
    Protocol version 3 - Summary of Changes: - Typographical and administrative changes - Updated and added new exclusion criteria - Clarified Rolling 6 Dose Evaluation Decision Rules - Added details on which blast count will be used to choose the cohort for a subject - Added that subjects must have a full neurological assessment prior to pre-conditioning (Day -7) - Amended central laboratory for MRD analysis from Great Ormond Street to Bristol Genetics Laboratory - Updated Management of CRS text - Updated concomitant medications and therapies
    02 Feb 2018
    Protocol version 4 - Summary of Changes: - Typographical and administrative changes - Updated schedule of events - Added up to 3 dose levels for Phase 1 and clarified that each dose level will have 2 cohorts - Added interim analysis on safety and preliminary efficacy - Updated study product wording for AUTO3 - Changed dose evaluation to dose escalation - Increased the number of patients needed for Phase I from 12-18 to 18-30. And increased the total number of patients needed for the whole study from 50 to 62 - Modified pre-conditioning regimen - Timing of 2nd split dose reduced from 14 days (+/- 7d) to 5-10 days - Updates to inclusion and exclusion criteria - Addition of available clinical data in the first 3 patients treated with CD19/CD22 CAR-positive T cells - Clarification of use of data from re-treated patients - SEC recommended to declared the Cohort 1 dose as safe and escalate dose for subsequent patients to 3x10^6 CD19/CD22-positive CAR-T cells/kg and further if needed to establish a RP2D - Modified text based on recently published data indicating that patients at risk of severe CRS or neurotoxicity develop signs and symptoms very early and early dosing of the second fraction between day 5-10 is likely to maximise the potential effect of pre-conditioning induced cytokines on AUTO3 without increasing the risk of severe toxicity - Updated DLT criteria - Clarified text regarding patients with ≥25% blasts can be treated with single doses if both single and split doses are determined to be safe - Revised Safety Stopping Criteria - Dosing caveat added to increase patient safety - Updated text regarding re-treatment of patients - Updated the CRS management guidelines - Update the tocilizumab dosing guidelines to match the current label - Revised concomitant medications text - Updated dietary and lifestyle restrictions - Clarified interim analysis text - Clarified study discontinuation text - Clarified monitoring text
    11 May 2018
    Protocol version 5 - Summary of Changes: - Clarified exclusion criteria - Updated schedule of events
    10 Oct 2018
    Protocol version 6 - Summary of Changes: (US only; not implemented) - Typographical changes - Revised text regarding single or split doses based on disease burden, but clarified they will be analysed as one group - Updated DLT definition based on FDA recommendation - Made corrections to the risks and mitigations section
    29 Mar 2019
    Protocol version 7 - Summary of Changes: (implemented in v. 8) - ‘Young adult’ has been replaced by ‘adult’ - Inclusion of a potential 4th dose level, that increases the total number of paediatric/young adult patients required for Phase I to 24-36 - Inclusion of an adult cohort (≥25 years), which adds 12-24 patients into Phase I - Update to Infectious Disease Screening - Reduction of blood volume required for RCR testing and insertional mutagenesis from 10ml to 5 - Update to paediatric/young adult exclusion criteria - Update of window for DLT period at Day 30 to ±3 days - The recommended in-patient stay after AUTO3 dosing in Phase I has been reduced from 30 (-3/+5) days to 14 days, or longer if necessary. In Phase II the duration of admission to hospital will be based on emerging data and the patient’s condition. Patient may be discharged before 14 days or treated as out patients - MRD will now be analysed at all time points by both PCR and flow - Bone marrow and cerebrospinal fluid tests at Day 0 removed - Frequency of blood tests for cytokines and CAR T cells reduced - Immunological profiling will be done in Phase I only - Schedule of assessments updated - Update to the clinical data in AUTO3-PA1 to new data - Update to secondary objectives and endpoints - The SEC has agreed that Cohort 2b (3x10^6/kg split dose) should be closed after 1 patient as it is deemed sub-therapeutic - A minimum of 6 patients need to be treated in a cohort before it can be declared as the phase 2 dose - Updated DLT definition - Updated text in risks and mitigation section - Clarification of patients going on hold before dosing - Update to information on the administration of AUTO3 - New text added to Monitoring During and After Drug Administration section - Definitions of relapse disease have been clarified - New text added for HRQOL measures and bridging therapy - New CRS/MAS treatment option - Updated Lee et al, 2018 guidance - CTCAE version updated to v5.
    10 May 2019
    Protocol version 8 - Summary of Changes: - The recommended in-patient stay after AUTO3 dosing has been returned from 14 days to 30 days (±3), or longer if necessary for monitoring and management, per MHRA request - The following text was deleted: AEs such as severe cytopenias that require re-hospitalization within 30 (±3) days of AUTO3 because the patient was discharged early should not be automatically reported as SAEs unless clinically indicated ex febrile neutropenia - Reporting of prolonged Grade 4 cytopenia lasting more than 60 days: text moved and clarification added - BMA immunophenotyping and flow MRD tests at screening

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    29 Sep 2019
    Recruitment halted on 29-Sep-2019 and not reopened. Patients were followed to completion (withdrawal).
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Early completion of the study leading to small numbers of patients analyzed from the Phase I part of the study.
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2022 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA