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B Acute Lymphoblastic LeukemiaPhase 1/2AMELIANCT03289455

CD19 /22 CAR T Cells (AUTO3) for the Treatment of B Cell Acute Lymphoblastic Leukemia (ALL)

A Phase 1/2 study testing AUTO3 (CD19/22 CAR T cells in people with B Acute Lymphoblastic Leukemia and Recurrent Childhood Acute Lymphoblastic Leukemia, run by Autolus Limited at 3 sites in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The purpose of this study is to test the safety and efficacy of AUTO3, a CAR T cell treatment targeting CD19 and CD22 in paediatric or young adult patients with relapsed or refractory B cell acute lymphoblastic leukaemia. Read more about this study

Who is it for?
Ages 1 year to 24 years
What is being tested?
AUTO3 (CD19/22 CAR T cells
Could I receive a placebo?
No, everyone receives an active treatment
How many people
23 participants
Where
3 sitesUnited Kingdom
Study dates
26 Jun 2017to 18 May 2020
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 year to 24 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • Male or female patients aged 1-24 years with high risk (HR) relapsed/refractory B-lineage ALL, AND:
  • Any bone marrow (BM) relapse or central nervous system (CNS) relapse with detectable BM disease after allogeneic stem cell transplant (SCT) and must be ≥6 months from SCT at the time of AUTO3 infusion; OR,
  • HR first relapse; OR,
  • Standard risk relapse patients with HR cytogenetics; OR,
  • Second or greater relapse; OR,
  • BM minimal residual disease (MRD) ≥10-³ prior to planned SCT; OR,
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  • Any on-treatment relapse in patients aged 16-24 years.
  • (Phase II Only - Criteria in addition to those described above:)
  • Primary refractory disease; 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.
  • Documentation of CD19 and or CD22 expression on leukaemic blasts in the BM, peripheral blood, or cerebrospinal fluid within 3 months of screening.
  • Detectable disease in the BM at a level ≥10-⁴ (Phase I only).
  • Absolute lymphocyte count ≥0.5 x 10⁹/L.
  • Adequate renal, hepatic, pulmonary, and cardiac function.
  • Karnofsky (age ≥10 years) or Lansky (age <10 years) score ≥50%.
  • Willing and able to give written, informed consent to the current study (patient and/or parent or legal guardian).

Who cannot join

  • Isolated extra-medullary disease relapse.
  • Active CNS involvement of ALL (CNS Grade 3 per National Comprehensive Cancer Network guidelines).
  • Active infectious bacterial or viral disease requiring IV anti-microbials for treatment.
  • Females who are pregnant or lactating.
  • Females of child-bearing potential and post pubertal male participants who are unwilling to use highly effective methods of contraception for a period of 1 year after the AUTO3 infusion.
  • Inability to tolerate leukapheresis.
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  • Prior CD19 or CD22 targeted therapy with Grade 4 toxicity or ≥refractory Grade 3 cytokine release syndrome (CRS) or ≥Grade 3 drug related CNS toxicity.
  • Pre-existing significant neurological disorder.
  • Stem Cell Transplant patients only: active significant acute graft versus host disease (GVHD) or moderate/severe chronic GVHD requiring systemic steroids or other immunosuppressant within 4 weeks of enrolment.
  • The following medications are excluded:
  • Steroids: Therapeutic doses of steroids must be stopped >72 hours prior to AUTO3 infusion and leukapheresis. However, physiological replacement doses of steroids are allowed: <12 mg/m2/day hydrocortisone or equivalent.
  • Allogeneic cellular therapy: Any donor lymphocyte infusions must be completed >6 weeks prior to AUTO3 infusion.
  • Graft versus host disease therapies: Any drug used for GVHD must be stopped >4 weeks prior to AUTO3 infusion.
  • Chemotherapy: Should be stopped 1 week prior to leukapheresis and 2 days prior to starting pre-conditioning chemotherapy.
  • Known allergy to albumin, dimethyl sulfoxide, cyclophosphamide or fludarabine.
  • For AUTO3 Infusion: Patients meeting any of the following exclusion criteria will not be treated with AUTO3 or treatment will be delayed until they no longer meet these criteria:
  • Severe intercurrent infection.
  • Requirement for supplementary oxygen.
  • Allogeneic transplant recipients with active significant acute GVHD overall Grade ≥II or moderate/severe chronic GVHD requiring systemic steroids.

Trial locations and contacts

3 sites in 1 country.

United Kingdom3 sites
  • Great Ormond Street Hospital for Children NHS Foundation Trust

    London

  • University College London Hospitals NHS Foundation Trust

    London

  • Royal Manchester Children's Hospital

    Manchester

Other trials in United Kingdom

About this study

Official title: 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

The purpose of this study is to test the safety and efficacy of AUTO3, a CAR T cell treatment targeting CD19 and CD22 in paediatric or young adult patients with relapsed or refractory B cell acute lymphoblastic leukaemia.

Read the detailed description

The study will consist of 2 phases, a Phase I or dose escalation phase and a Phase II or expansion phase. Paediatric or young adult patients with relapsed or refractory B cell ALL will be enrolled in both phases of the study. Eligible patients will undergo leukapheresis in order to harvest T cells, which is the starting material for the manufacture of the autologous CAR T product AUTO3 which is a CD19 and CD22 dual targeting CAR T cell product. Following pre-conditioning by a chemotherapeutic regimen, the patient will receive AUTO3 intravenously as a single or split dose and will then enter a 24-month follow-up period.

Being tested
AUTO3 (CD19/22 CAR T cells
Keywords
Acute Lymphoblastic Leukaemia, CD19 Positive, CD22 Positive, Relapsed Acute Lymphoblastic Leukaemia, Refractory Acute Lymphoblastic Leukaemia, AUTO3
Medical subject headings
Burkitt Lymphoma, Precursor Cell Lymphoblastic Leukemia-Lymphoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AUTO3 (CD19/22 CAR T cellsBiological

    Following preconditioning with chemotherapy (cyclophosphamide and fludarabine) patients will be treated with 1 to 5.0 x 10⁶/kg CD19/CD22 Chimeric Antigen Receptor (CAR) positive T cells as a single or split dose.

Study groups in NCT03289455
Study groupRoleWhat they receive
AUTO3ExperimentalPaediatric patients with relapse or refractory B-cell ALL
Receives: Biological: AUTO3 (CD19/22 CAR T cells

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Patients With Grade 3-5 Toxicities Occurring Within the Dose Limiting Toxicity (DLT) Period of AUTO3 Infusion

    Measured: Within 30 days (+/- 3 days) after the last dose of AUTO3.

  2. Number of Patients With Dose Limiting Toxicity (DLT) of AUTO3

    DLT was defined as i) any new non-hematological adverse event (AE) of Grade 3 or higher toxicity using the NCI CTCAE (version 5.0), which was probably or definitely related to AUTO3 therapy, which occurred within the DLT evaluation period, and which failed to resolve to Grade 2 or better within 14 days, despite appropriate supportive measures; ii) Grade 4 cytokine release syndrome (CRS) or neurotoxicity, cerebral edema, or Grade 3 neurotoxicity (including cerebral edema) that lasted >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 could not be managed with conventional supportive measures or which in the opinion of the Safety Evaluation Committee (SEC) necessitated dose reduction or other modification to trial treatment to avoid a similar hazard in future patients.

    Measured: Within 30 days (+/- 3 days) after the last dose of AUTO3.

  3. Number 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)).

    Morphological response evaluations were based on the response criteria for ALL according to the NCCN guidelines version 2.2014. Minimal residual disease-negative status was achieved if MRD was <10^-4 (0.01%) by PCR amplification of individual rearrangements of Ig genes and/or flow cytometry MRD testing.

    Measured: Within 30 days (+/- 3 days) post AUTO3 infusion

Secondary outcomes (8)
  1. Feasibility of Generating AUTO3: Number of Patients' Cells Successfully Manufactured as a Proportion of the Number of Patients Undergoing Leukapheresis

    Feasibility of product generation was examined by assessing the number of AUTO3 successfully manufactured as a fraction of the number of patients undergoing leukapheresis (all patients screened).

    Measured: Up to 8 weeks post leukapheresis

  2. Event-Free Survival (EFS) by Morphological Analysis

    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.

    Measured: Up to 2 years

  3. Number of Patients With CD19- and/or CD22-negative Relapse

    Measured: Up to 2 years

  4. Relapse-Free Survival (RFS) by Morphological Analysis

    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.

    Measured: Up to 2 years

  5. Overall Survival (OS)

    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.

    Measured: Up to 2 years after the last patient was infused

  6. Expansion of AUTO3 Following Adoptive Transfer

    Expansion of AUTO3 was measured as the median peak (Cmax) of transgene levels in the peripheral blood after AUTO3 infusion

    Measured: Up to 2 years

  7. Persistence of AUTO3 Following Adoptive Transfer

    Persistence of AUTO3 was measured by quantitative polymerase chain reaction (qPCR) 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).

    Measured: Up to 2 years

  8. Duration of B Cell Aplasia

    Depletion of circulating B cells assessed by flow cytometry at a range of time points in the peripheral blood

    Measured: Up to 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Sep 2017
  2. Study start26 Jun 2017
  3. Primary completion18 May 2020
  4. Study completion18 May 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
23 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03289455
Sponsor's protocol ID
AUTO3-PA1
Other IDs
2016-004680-39, 2016
Acronym
AMELIA
Status last verified
Jan 2021
First submitted
11 Sep 2017
Last updated
1 Feb 2021
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Roddie C, Lekakis LJ, Marzolini MAV, Ramakrishnan A, Zhang Y, Hu Y, Peddareddigari VGR, Khokhar N, Chen R, Basilico S, Raymond M, Vargas FA, Duffy K, Brugger W, O'Reilly MA, Wood L, Linch DC, Peggs KS, Bachier C, Budde EL, Lee Batlevi C, Bartlett N, Irvine D, Tholouli E, Osborne W, Ardeshna KM, Pule MA. Dual targeting of CD19 and CD22 with bicistronic CAR-T cells in patients with relapsed/refractory large B-cell lymphoma. Blood. 2023 May 18;141(20):2470-2482. doi: 10.1182/blood.2022018598.

    PubMed 36821767

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing AUTO3 (CD19/22 CAR T cells in people with B Acute Lymphoblastic Leukemia and Recurrent Childhood Acute Lymphoblastic Leukemia, run by Autolus Limited at 3 sites in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 1 Feb 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Patients With Grade 3-5 Toxicities Occurring Within the Dose Limiting Toxicity (DLT) Period of AUTO3 Infusion (time frame: Within 30 days (+/- 3 days) after the last dose of AUTO3.). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03289455, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Feb 2021.

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