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    EudraCT Number:2016-004680-39
    Sponsor's Protocol Code Number:AUTO3-PA1
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-03-03
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2016-004680-39
    A.3Full title of the trial
    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 Adult Patients with Relapsed or Refractory B Cell Acute Lymphoblastic Leukaemia.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase I/II study to evaluate AUTO3 in children and adults with acute lymphoblastic leukaemia who have previously received approved treatment(s).
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberAUTO3-PA1
    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 SponsorAutolus Limited
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAutolus Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAutolus Limited
    B.5.2Functional name of contact pointProject Manager
    B.5.3 Address:
    B.5.3.1Street AddressForest House, 58 Wood Lane
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeW12 7RZ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number442038296230
    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 nameAUTO3
    D.3.2Product code AUTO3
    D.3.4Pharmaceutical form Dispersion for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNn/a
    D.3.9.1CAS number n/a
    D.3.9.2Current sponsor codeAUTO3
    D.3.9.3Other descriptive nameCD19/CD22-CAR POSITIVE T CELLS
    D.3.9.4EV Substance CodeSUB185831
    D.3.10 Strength
    D.3.10.1Concentration unit U unit(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number1.8 to 700
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    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) Yes
    D. cell therapy medicinal product No
    D. therapy medical product Yes
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    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
    Acute lymphoblastic leukaemia (ALL)
    E.1.1.1Medical condition in easily understood language
    Cancer of white blood cells in the bone marrow.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10000845
    E.1.2Term Acute lymphoblastic leukemia
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10063625
    E.1.2Term Acute lymphoblastic leukemia recurrent
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase I: Assess the safety and tolerability of AUTO3 AUTO3 in both paediatric and adult patients and identify the recommended Phase II dose, dosing schedule & maximum tolerated dose, where applicable.
    Phase II: Evaluate the anti-leukaemic effect of AUTO3 in paediatric and young adult patients (aged 1-24 years).
    E.2.2Secondary objectives of the trial
    - Evaluate safety and tolerability of AUTO3
    - Evaluate the clinical efficacy of AUTO3
    - Evaluate feasibility of generating AUTO3
    - Assess the expansion & persistence of AUTO3
    - Duration of B cell aplasia
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Paediatric and young adult patients
    1. Male or female paediatric and young adults (age 1-24 years) with high risk relapsed or refractory B-cell Acute Lymphoblastic Leukaemia
    2. Documented CD19 and or CD22 expression
    3. Detectable disease in the bone marrow (Phase I) at enrolment
    4. Absolute Lymphocyte Count ≥0.5 x 10e9/l at enrolment
    5. Adequate renal, hepatic, pulmonary & cardiac function including:
    - Left ventricular shortening fraction ≥28% confirmed by ECHO, or left ventricular ejection fraction (LVEF) ≥45% confirmed by ECHO.
    - Baseline oxygen saturation >92% on room air.
    6. Karnofsky (age 10-24 years) or Lansky (age < 10 years) score ≥ 50%
    7. Willing and able to give written informed consent/assent.

    Phase II Only:
    8. Primary refractory disease defined as MRD >5% blasts in the BM by flow cytometry or molecular assay following frontline induction therapy OR
    - Patients with Philadelphia chromosome-positive ALL are eligible if they are intolerant to or have failed 2 lines of tyrosine kinase inhibitor (TKI) therapy, or if TKI therapy is contraindicated OR
    - Isolated CNS relapse but with ≤CNS grade 2 disease at time of enrolment

    Adult patients
    1. Age 25 or older
    2. Eastern cooperative oncology group performance status of 0 or 1
    3. Relapsed or refractory B-precursor ALL defined as one of the following:
    4. Patients with Philadelphia chromosome positive ALL are eligible if they are intolerant to or have failed 2 lines of TKI therapy, or if TKI therapy is contraindicated
    5. Documentation of CD19 and/ or CD22 expression on leukaemic blasts in the BM, peripheral blood, or CSF by flow cytometry within 3 months of screening
    6. For females of childbearing potential, a negative serum or urine pregnancy test
    7. For females who are not postmenopausal or who are not surgically sterile & males, two methods of contraception should be used
    8. Absolute lymphocyte count ≥0.5 x 109/L at enrolment
    9. Adequate renal, hepatic, pulmonary, and cardiac function defined as:
    - LVEF ≥45% confirmed by ECHO or MUGA.
    - Baseline oxygen saturation >92% on room air

    E.4Principal exclusion criteria
    Paediatric and young adult patients
    1. Isolated extramedullary disease relapse (in Phase II, patients with isolated CNS relapse post-SCT or pre-SCT if high risk, aged 16-24 years on therapy relapse or ≥ 2nd relapse with ≤CNS grade 2 disease at time of enrolment)
    2. Active CNS involvement of ALL, defined by CNS Grade 3 per National Comprehensive Cancer Network guidelines. Patients developing CNS Grade 3 disease at any time after enrolment will also be excluded
    3. Active infectious bacterial or viral disease requiring treatment.
    4. Females who are pregnant or lactating.
    5. Females of child-bearing potential and post-pubertal males who unwilling to use highly effective methods of contraception during the treatment period and 1 year after AUTO3 infusion.
    6. Pre-existing significant neurological disorder
    7. Stem Cell Transplant patients only: active significant (overall Grade ≥II, Seattle criteria) acute graft versus host disease (GVHD) or moderate/severe chronic GVHD (National Institutes of Health [NIH] consensus criteria) requiring systemic steroids or other immunosuppressant within 4 weeks of enrolment
    8. The following treatments are excluded:
    - Steroids: Therapeutic doses must be stopped >72 hours prior to AUTO3 infusion and leukapheresis.
    - Allogeneic cellular therapy: Any donor lymphocyte infusions must be completed >6 weeks prior to AUTO3 infusion
    - GVHD therapies: Any drug used for GVHD must be stopped >4 weeks prior to AUTO3 infusion
    - Chemotherapy: Stopped 1 week prior to leukapheresis and 2 days prior to starting pre-conditioning chemotherapy
    - Intrathecal therapy: Methotrexate within 4 weeks and other intrathecal chemotherapy (eg Ara-C) within 2 weeks prior to starting pre conditioning chemotherapy.
    - Live vaccine ≤ 4 weeks prior to enrolment.
    9. Known allergy to albumin, dimethyl sulfoxide, cyclophosphamide or fludarabine.

    Adult patients
    1. Isolated extramedullary disease
    2. Diagnosis of Burkitt's leukaemia/lymphoma or chronic myelogenous leukaemia lymphoid blast crisis
    3. Females who are pregnant or lactating
    4. History or presence of clinically relevant CNS pathology within 3 months prior to enrolment, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, uncontrolled mental illness, or psychosis
    5. Presence of CNS-3 disease or CNS-2 disease with neurological changes. Patients developing CNS Grade 3 disease or symptomatic CNS-2 disease at any time after enrolment will also be excluded
    6. Clinically significant, uncontrolled heart disease or a recent cardiac event
    7. Patients with a history or evidence of pulmonary embolism requiring ongoing therapeutic anticoagulation at the time of pre-conditioning
    8. Patients with active gastrointestinal bleeding
    9. Patients with any major surgical intervention in the last 3 months
    10. Active infectious bacterial or viral disease or fungal requiring treatment with i.v. antimicrobials
    11. History of autoimmune disease resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 24 months. Any autoimmune disease with CNS involvement
    12. History of other malignant neoplasms unless disease free for at least 24 months
    13. History of concomitant genetic syndrome such as Fanconi anaemia, Shwachman-Diamond syndrome, Kostmann syndrome or any other known BM failure syndrome
    14. Stem cell transplant patients only: Active significant acute GVHD or moderate/severe chronic GVHD) requiring systemic steroids or other immunosuppressants within 4 weeks of enrolment.
    15. Excluded medications:
    - Steroids: Therapeutic doses of corticosteroids within 7 days of leukapheresis or 72 hours prior to AUTO3 administration
    - Immunosuppression: Immunosuppressive medication must be stopped ≥2 weeks prior to leukapheresis or AUTO3 infusion
    - Allogeneic cellular therapy: Any donor lymphocyte infusions must be completed >6 weeks prior to AUTO3 infusion
    - GVHD therapies: Any drug used for GVHD must be stopped >4 weeks prior to AUTO3 infusion
    - Chemotherapy including TKIs for Philadelphia chromosome positive ALL: Should be stopped 1 week prior to leukapheresis or 2 days prior to starting pre-conditioning chemotherapy
    - Treatment with alemtuzumab within 6 months prior to leukapheresis, or treatment with clofarabine or cladribine within 3 months prior to leukapheresis
    - Live vaccine ≤ 4 weeks prior to enrolment
    - Intrathecal therapy: Methotrexate within 4 weeks and other intrathecal chemotherapy (e.g. Ara-C) within 2 weeks prior to starting pre-conditioning chemotherapy
    - Systemic inhibitory/stimulatory immune checkpoint - At least 2 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy prior to enrolment
    16. Research participants receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy

    E.5 End points
    E.5.1Primary end point(s)
    Phase I:
    - Incidence of Grade 3-5 toxicity within the dose limiting toxicity (DLT) period of AUTO3 infusion
    - Frequency of dose limiting toxicity of AUTO3
    Phase II:
    - Proportion of patients achieving morphological remission (Complete Response [CR] or complete response with incomplete recovery of counts [CRi]) and MRD-negative response in BM within approx. 30 days post AUTO3 infusion
    E.5.1.1Timepoint(s) of evaluation of this end point
    - Safety endpoint evaluations will be conducted throughout the study
    - Grade 3-5 toxicity within the DLT period
    - MRD-negative response captured approx. 30 days post-dose
    - Morphological remission captured at time of CR/CRi
    E.5.2Secondary end point(s)
    - Frequency and severity of AEs and SAEs.
    - Incidence and duration of severe hypogammaglobulinemia
    - Proportion of patients that AUTO3 can be generated
    - Proportion of patients achieving morphological remission (CR or CRi) and MRD-negative response in bone marrow approx. 30 days post-AUTO3 infusion
    - Proportion of patients in molecular remission without further therapy.
    - Relapse Free Survival (RFS), Event Free Survival (EFS), Progression-Free Survival (PFS) and Overall Survival (OS) following first AUTO3 treatment
    - Incidence of CD19 and or CD22 negative escape
    - Quantitative PCR and/or flow cytometry at a range of time points in the peripheral blood and bone marrow
    - Depletion of circulating B cell assessments
    - Health-related quality of life (HRQOL)
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Safety endpoints and AUTO3 monitoring evaluations will be conducted throughout the study
    - Feasibility to generate AUTO3 assessed after manufacture
    - Morphological remission and MRD-negative response assessed approx. 30 days post AUTO3 dose
    - RFS, EFS at 6, 12 and 24 months
    - Progression free survival (PFS) and overall survival (OS) measured from last AUTO3 treatment to relapse/disease progression and death, respectively
    - Molecular remission at 6 months, 1 & 2 years post AUTO3 treatment
    - Biomarker/PD measurements taken at screening, pre-conditioning, day 0, 2, 5, 7, 9, 12, 14, 21, 30 and 2, 3, 4, 6, 8, 10, 12, 15, 18, 21 & 24 months post treatment
    - HRQOL at 1, 3, 6, 8, 12 and 24 months
    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 Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open 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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Yes
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the trial will be 24 months after the last patient has received AUTO3 infusion (or earlier, if appropriate).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days0
    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: 100
    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. of subjects for this age range: 2
    F.1.1.5Children (2-11years) Yes
    F. of subjects for this age range: 30
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 24
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4
    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 No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F. of subjects incapable of giving consent
    Paediatric population
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state70
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 100
    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 be eligible to be followed up for up to 15 years post AUTO3
    infusion on a separate long-term follow-up protocol. Otherwise, they
    would be treated per their physician's guidance for their disease
    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 Decision2017-06-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-06-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-05-18
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