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    Summary
    EudraCT Number:2016-004682-11
    Sponsor's Protocol Code Number:AUTO3-DB1
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-06-20
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2016-004682-11
    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 with Anti PD-1 Antibody in Patients with Relapsed or Refractory Diffuse Large B Cell Lymphoma.
    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 adults with
    Diffuse Large B Cell Lymphoma who have previously received approved treatment(s) and subsequently progressed.
    A.3.2Name or abbreviated title of the trial where available
    ALEXANDER
    A.4.1Sponsor's protocol code numberAUTO3-DB1
    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.5.6E-mailclinicaltrials@autolus.com
    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 number15 to 900
    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.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) 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.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name KEYTRUDA
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameKEYTRUDA
    D.3.4Pharmaceutical form Solution 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 INNPEMBROLIZUMAB
    D.3.9.1CAS number 1374853-91-4
    D.3.9.3Other descriptive nameanti-programmed cell death1 (PD1) antibody
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsed or refractory Diffuse Large B Cell Lymphoma (DLBCL) and large B cell lymphoma subsets
    E.1.1.1Medical condition in easily understood language
    Diffuse large B cell lymphoma and subsets. A form of cancer of the white blood cells
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10012822
    E.1.2Term Diffuse large B-cell lymphoma refractory
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10012819
    E.1.2Term Diffuse large B-cell lymphomas
    E.1.2System Organ Class 100000004851
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10012818
    E.1.2Term Diffuse large B-cell lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10036711
    E.1.2Term Primary mediastinal large B-cell lymphomas
    E.1.2System Organ Class 100000004851
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10036710
    E.1.2Term Primary mediastinal large B-cell lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase I: Assess the safety and tolerability of AUTO3 with pembrolizumab and identify the recommended Phase II dose & maximum tolerated dose, where applicable.
    Phase 2: To evaluate the safety, tolerability and anti-tumour effect of AUTO3 and pembrolizumab.
    E.2.2Secondary objectives of the trial
    - Evaluate the overall safety and tolerability of AUTO3 with pembrolizumab
    - Evaluate the clinical efficacy of AUTO3 with pembrolizumab
    - Evaluate feasibility of generating AUTO3
    - Assess the expansion & persistence after AUTO3 treatment
    - Duration of B cell aplasia
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female, aged ≥18 years that provide written informed consent.
    2. Eastern Cooperative Oncology Group performance status 0 to 1.
    3. Histologically confirmed DLBCL and large B cell lymphoma (at last relapse) and permitted subsets.
    4. Chemotherapy-refractory disease or Relapse after at least two lines of therapy or after ASCT.
    5. PET-positive disease per Lugano classification.
    6. Females of childbearing potential must have a negative serum or urine pregnancy test at screening, prior to pre-conditioning and confirmed before receiving the first dose of AUTO3.
    7. Adequate renal, hepatic, pulmonary, and cardiac function defined as:
    a. Creatinine clearance ≥40 cc/min
    b. Serum alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) ≤2.5 x ULN.
    c. Total bilirubin ≤1.5 x ULN.
    d. Left Ventricular Ejection Fraction (LVEF) ≥50% unless the institutional lower limit of normal is lower.
    e. Baseline oxygen saturation >92% on room air and ≤Grade 1 dyspnoea.
    8. Patient has adequate bone marrow function and meets the following criteria:
    a. Absolute neutrophil count ≥1.0 x 10e9/L.
    b. Absolute lymphocyte count ≥0.3 x 10e9/L (at enrolment and prior to leukapheresis).
    c. Haemoglobin ≥80 g/L;
    d. Platelets ≥75 x 10e9/L.
    E.4Principal exclusion criteria
    1. Prior allogeneic haematopoietic stem cell transplantation.
    2. Females who are pregnant or lactating.
    3. History or presence of clinically relevant central nervous system (CNS) pathology within 3 months prior to enrolment.
    4. Patients with active CNS involvement by malignancy.
    5. Clinically significant, uncontrolled heart disease or a recent cardiac event.
    6. Active bacterial, viral disease or fungal infection requiring systemic treatment.
    7. History of autoimmune disease resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents in the last 2 years.
    8. Evidence of active pneumonitis on chest computed tomography (CT) scan at screening or history of drug-induced pneumonitis, idiopathic pulmonary fibrosis, organising pneumonia, idiopathic pneumonitis.
    9. Prior treatment with therapy targeting programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated protein 4 (CTLA 4) or prior treatment with tumour necrosis factor receptor superfamily (TNFRSF) agonists and CD357 (glucocorticoid-induced tumour necrosis factor receptor family related protein) within 6 weeks prior to AUTO3 infusion.
    10. Prior CD19 or CD22 targeted therapy.
    11. The following medications are excluded:
    a. Steroids: Therapeutic doses of corticosteroids within 7 days of leukapheresis or 72 hours prior to AUTO3 administration.
    b. Immunosuppression: Immunosuppressive medication must be stopped ≥2 weeks prior to leukapheresis or AUTO3 infusion.
    c. Cytotoxic chemotherapies within 2 weeks of infusion and 1 week prior to leukapheresis.
    d. Antibody therapy use including anti-CD20 therapy within 4 weeks prior to infusion, or 5 half-lives of the respected antibody, whichever is shorter.
    e. Granulocyte-colony stimulating factor (G-CSF) less than 10 days prior to leukapheresis.
    f. Live vaccine ≤4 weeks prior to enrolment.
    g. Prophylactic intrathecal therapy: Methotrexate within 4 weeks and other intrathecal chemotherapy within 2 weeks prior to starting pre-conditioning
    chemotherapy.
    12. Prior radiation therapy within 4 weeks or chest within 24 weeks of AUTO3 infusion .
    13. Patients receiving any other investigational agents or concurrent biological, chemotherapy or radiation therapy.
    14. Known allergy to albumin, dimethyl sulphoxide, cyclophosphamide or fludarabine, anti-PD-1 antibody or tocilizumab.
    15. Contraindications to receive anti-PD1 antibody will be excluded from cohorts requiring administration this administration.

    Phase I expansion only:
    16. Subjects who do not have adequate caregiver support for outpatient care.
    17. Subjects who are staying greater than 60 minutes (or whatever is permissible per institutional outpatient transplant SOP) from the clinical trial site at the time of treatment.

    E.5 End points
    E.5.1Primary end point(s)
    Phase I:
    - Incidence of Grade 3-5 toxicity within 75 days of AUTO3 infusion
    - Frequency of dose limiting toxicity of AUTO3
    Phase II:
    - Best overall response 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 captured 75 days post dose
    - Overall response at 1, 3, 6, 9, 12, 18 and 24 months post AUTO3 infusion.
    E.5.2Secondary end point(s)
    -To assess the overall safety and tolerability of AUTO3 with pembrolizumab: Frequency and severity of all AEs and SAEs. Incidence and duration of severe hypogammaglobulinaemia.
    -To evaluate the feasibility of generating the ATIMP, AUTO3: Proportion of patients for whom an AUTO3 product can be generated (feasibility).
    -To evaluate the overall clinical efficacy of AUTO3 with pembrolizumab: Determine the CR rate following treatment with AUTO3. To evaluate clinical outcomes including duration of response (DOR), DFS, PFS and OS.
    -To determine the expansion and persistence of AUTO3 following adoptive transfer.
    - Duration of B cell aplasia. Polymerase Chain Reaction (PCR) and/or flow cytometry at a range of time points in the peripheral blood depletion of circulating B cells assessed by flow cytometry at a range of time points in the peripheral blood
    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
    - Objective response at 1, 3, 6 and 24 months post AUTO3 infusion
    - Duration of response from first observation of complete or partial response to progression, relapse or death
    - Disease free survival from first observation of complete response to progression or relapse or death
    - Progression free and overall survival measured from last AUTO3 treatment to relapse/disease progression and death, respectively
    - PK/PD/biomarker measurements taken at screening, pre-conditioning, day -5, 1, 4, 7, 10, 12, 14, 16, 18, 20, 28, 56 and at 3, 4, 5, 6, 9, 12, 15, 18 & 24 months post treatment.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA14
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    France
    Italy
    Spain
    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 years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 101
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 70
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state57
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 114
    F.4.2.2In the whole clinical trial 171
    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 treatment.
    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 Opinion2017-07-19
    P. End of Trial
    P.End of Trial StatusOngoing
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