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

• Sponsor: Autolus Limited (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03289455
• Collaborator: (none)
• Enrollment: 23
• Locations: 3
• Arm: 1
• Actual Duration (Months): 34.7
• Patients Per Site: 7.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
B Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Refractory Childhood Acute Lymphoblastic Leukemia; B-cell Acute Lymphoblastic Leukemia	Biological: AUTO3 (CD19/22 CAR T cells	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Jun 26, 2017
• Actual Primary Completion Date: May 18, 2020
• Actual Study Completion Date: May 18, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AUTO3 Paediatric patients with relapse or refractory B-cell ALL	Biological: AUTO3 (CD19/22 CAR T cells; 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.

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Grade 3-5 Toxicities Occurring Within the Dose Limiting Toxicity (DLT) Period of AUTO3 Infusion [Within 30 days (+/- 3 days) after the last dose of AUTO3.]

2. Number of Patients With Dose Limiting Toxicity (DLT) of AUTO3 [Within 30 days (+/- 3 days) after the last dose 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.

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)). [Within 30 days (+/- 3 days) post AUTO3 infusion]

   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.

Secondary Outcome Measures

1. Feasibility of Generating AUTO3: Number of Patients' Cells Successfully Manufactured as a Proportion of the Number of Patients Undergoing Leukapheresis [Up to 8 weeks post 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).

2. Event-Free Survival (EFS) by Morphological Analysis [Up to 2 years]

   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.

3. Number of Patients With CD19- and/or CD22-negative Relapse [Up to 2 years]

4. Relapse-Free Survival (RFS) by Morphological Analysis [Up to 2 years]

   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.

5. Overall Survival (OS) [Up to 2 years after the last patient was infused]

   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.

6. Expansion of AUTO3 Following Adoptive Transfer [Up to 2 years]

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

7. Persistence of AUTO3 Following Adoptive Transfer [Up to 2 years]

   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).

8. Duration of B Cell Aplasia [Up to 2 years]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 24 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

1. Male or female patients aged 1-24 years with high risk (HR) relapsed/refractory

B-lineage ALL, AND:

1. 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,

2. HR first relapse; OR,

3. Standard risk relapse patients with HR cytogenetics; OR,

4. Second or greater relapse; OR,

5. BM minimal residual disease (MRD) ≥10-³ prior to planned SCT; OR,

6. Any on-treatment relapse in patients aged 16-24 years.

(Phase II Only - Criteria in addition to those described above:)

1. Primary refractory disease; OR,

2. 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,

3. Isolated CNS relapse but with ≤CNS Grade 2 disease at time of enrolment.

4. Documentation of CD19 and or CD22 expression on leukaemic blasts in the BM, peripheral blood, or cerebrospinal fluid within 3 months of screening.

5. Detectable disease in the BM at a level ≥10-⁴ (Phase I only).

6. Absolute lymphocyte count ≥0.5 x 10⁹/L.

7. Adequate renal, hepatic, pulmonary, and cardiac function.

8. Karnofsky (age ≥10 years) or Lansky (age <10 years) score ≥50%.

9. Willing and able to give written, informed consent to the current study (patient and/or parent or legal guardian).

Exclusion Criteria:

1. Isolated extra-medullary disease relapse.

2. Active CNS involvement of ALL (CNS Grade 3 per National Comprehensive Cancer Network guidelines).

3. Active infectious bacterial or viral disease requiring IV anti-microbials for treatment.

4. Females who are pregnant or lactating.

5. 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.

6. Inability to tolerate leukapheresis.

7. 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.

8. Pre-existing significant neurological disorder.

9. 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.

10. The following medications are excluded:

11. 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.

12. Allogeneic cellular therapy: Any donor lymphocyte infusions must be completed >6 weeks prior to AUTO3 infusion.

13. Graft versus host disease therapies: Any drug used for GVHD must be stopped >4 weeks prior to AUTO3 infusion.

14. Chemotherapy: Should be stopped 1 week prior to leukapheresis and 2 days prior to starting pre-conditioning chemotherapy.

15. 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:

1. Severe intercurrent infection.

2. Requirement for supplementary oxygen.

3. Allogeneic transplant recipients with active significant acute GVHD overall Grade ≥II or moderate/severe chronic GVHD requiring systemic steroids.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Great Ormond Street Hospital for Children NHS Foundation Trust	London		United Kingdom
2	University College London Hospitals NHS Foundation Trust	London		United Kingdom
3	Royal Manchester Children's Hospital	Manchester		United Kingdom

Sponsors and Collaborators

• Autolus Limited

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - May 10, 2019
• Statistical Analysis Plan - Jul 30, 2020

More Information

Publications

None provided.

• Responsible Party: Autolus Limited
• ClinicalTrials.gov Identifier: NCT03289455
• Other Study ID Numbers: AUTO3-PA1; 2016-004680-39
• First Posted: Sep 21, 2017
• Last Update Posted: Feb 1, 2021
• Last Verified: Jan 1, 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Autolus Limited: Acute Lymphoblastic Leukaemia; CD19 Positive; CD22 Positive; Relapsed Acute Lymphoblastic Leukaemia; Refractory Acute Lymphoblastic Leukaemia; AUTO3
• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid

Study Results

Participant Flow

Pre-assignment Detail	23 patients were screened, 20 patients leukapheresed and 15 patients were pre-conditioned with cyclophosphamide and fludarabine and infused with AUTO3 at 3 different dose levels.

Arm/Group Title	1x10^6 CD19/CD22 CAR-positive T Cells/kg	3x10^6 CD19/CD22 CAR-positive T Cells/kg	5x10^6 CD19/CD22 CAR-positive T Cells/kg
Arm/Group Description	Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells	All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells	Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells
Period Title: Overall Study
STARTED	4	5	6
COMPLETED	0	0	0
NOT COMPLETED	4	5	6

Baseline Characteristics

Arm/Group Title	1x10^6 CD19/CD22 CAR-positive T Cells/kg	3x10^6 CD19/CD22 CAR-positive T Cells/kg	5x10^6 CD19/CD22 CAR-positive T Cells/kg	Total
Arm/Group Description	Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells	All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells	Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells	Total of all reporting groups
Overall Participants	4	5	6	15
Age (Count of Participants)
<=18 years	4 100%	5 100%	6 100%	15 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%	2 40%	2 33.3%	4 26.7%
Male	4 100%	3 60%	4 66.7%	11 73.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	1 25%	0 0%	0 0%	1 6.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	3 75%	5 100%	6 100%	14 93.3%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United Kingdom	4 100%	5 100%	6 100%	15 100%
Karnofsky/Lansky score (percentage) [Median (Full Range) ]
Median (Full Range) [percentage]	95	90	100	90

Outcome Measures

1. Primary Outcome

Title	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.

Outcome Measure Data

Analysis Population Description

Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set)

Arm/Group Title	1x10^6 CD19/CD22 CAR-positive T Cells/kg	3x10^6 CD19/CD22 CAR-positive T Cells/kg	5x10^6 CD19/CD22 CAR-positive T Cells/kg
Arm/Group Description	Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells	All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells	Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells
Measure Participants	4	5	6
Count of Participants [Participants]	4 100%	4 80%	6 100%

2. Primary Outcome

Title	Number of Patients With Dose Limiting Toxicity (DLT) of AUTO3
Description	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.
Time Frame	Within 30 days (+/- 3 days) after the last dose of AUTO3.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1x10^6 CD19/CD22 CAR-positive T Cells/kg	3x10^6 CD19/CD22 CAR-positive T Cells/kg	5x10^6 CD19/CD22 CAR-positive T Cells/kg
Arm/Group Description	Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells	All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells	Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells
Measure Participants	4	5	6
Count of Participants [Participants]	0 0%	0 0%	0 0%

3. Primary Outcome

Title	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)).
Description	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.
Time Frame	Within 30 days (+/- 3 days) post AUTO3 infusion

Outcome Measure Data

Analysis Population Description

Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set).

Arm/Group Title	1x10^6 CD19/CD22 CAR-positive T Cells/kg	3x10^6 CD19/CD22 CAR-positive T Cells/kg	5x10^6 CD19/CD22 CAR-positive T Cells/kg
Arm/Group Description	Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells	All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells	Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells
Measure Participants	4	5	6
Count of Participants [Participants]	3 75%	5 100%	5 83.3%

4. Secondary Outcome

Title	Feasibility of Generating AUTO3: Number of Patients' Cells Successfully Manufactured as a Proportion of the Number of Patients Undergoing Leukapheresis
Description	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).
Time Frame	Up to 8 weeks post leukapheresis

Outcome Measure Data

Analysis Population Description

Patients who underwent leukapheresis. This outcome is measured before patients received infusion with AUTO3. Therefore, no split by dose cohort can be provided.

Arm/Group Title	AUTO3
Arm/Group Description	Pediatric and young adult patients with relapsed or refractory B cell ALL
Measure Participants	20
Count of Participants [Participants]	19 475%

5. Secondary Outcome

Title	Event-Free Survival (EFS) by Morphological Analysis
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.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set)

Arm/Group Title	1x10^6 CD19/CD22 CAR-positive T Cells/kg	3x10^6 CD19/CD22 CAR-positive T Cells/kg	5x10^6 CD19/CD22 CAR-positive T Cells/kg
Arm/Group Description	Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells	All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells	Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells
Measure Participants	4	5	6
Median (95% Confidence Interval) [months]	3.48	12.42	2.79

6. Secondary Outcome

Title	Number of Patients With CD19- and/or CD22-negative Relapse
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Patients who received at least 1 (complete or partial dose) of AUTO3 and had morphological relapses

Arm/Group Title	1x10^6 CD19/CD22 CAR-positive T Cells/kg	3x10^6 CD19/CD22 CAR-positive T Cells/kg	5x10^6 CD19/CD22 CAR-positive T Cells/kg
Arm/Group Description	Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells	All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells	Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells
Measure Participants	2	3	4
Count of Participants [Participants]	0 0%	2 40%	1 16.7%

7. Secondary Outcome

Title	Relapse-Free Survival (RFS) by Morphological Analysis
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.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set)

Arm/Group Title	1x10^6 CD19/CD22 CAR-positive T Cells/kg	3x10^6 CD19/CD22 CAR-positive T Cells/kg	5x10^6 CD19/CD22 CAR-positive T Cells/kg
Arm/Group Description	Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells	All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells	Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells
Measure Participants	4	5	6
Median (95% Confidence Interval) [months]	6.09	11.50	3.98

8. Secondary Outcome

Title	Overall Survival (OS)
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.
Time Frame	Up to 2 years after the last patient was infused

Outcome Measure Data

Analysis Population Description

Patients who received at least 1 (complete or partial) dose of AUTO3

Arm/Group Title	1x10^6 CD19/CD22 CAR-positive T Cells/kg	3x10^6 CD19/CD22 CAR-positive T Cells/kg	5x10^6 CD19/CD22 CAR-positive T Cells/kg
Arm/Group Description	Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells	All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells	Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells
Measure Participants	4	5	6
Median (95% Confidence Interval) [months]	10.17	25.20	NA

9. Secondary Outcome

Title	Expansion of AUTO3 Following Adoptive Transfer
Description	Expansion of AUTO3 was measured as the median peak (Cmax) of transgene levels in the peripheral blood after AUTO3 infusion
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Patients who received at least 1 (complete or partial) dose of AUTO3 and had evaluable cellular kinetics data (who had at least 1 cellular kinetics concentration post AUTO3 infusion above the lower limit of quantitation) (cellular kinetics analysis set)

Arm/Group Title	1x10^6 CD19/CD22 CAR-positive T Cells/kg	3x10^6 CD19/CD22 CAR-positive T Cells/kg	5x10^6 CD19/CD22 CAR-positive T Cells/kg
Arm/Group Description	Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells	All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells	Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells
Measure Participants	4	5	4
Median (Full Range) [vector copies/ug DNA]	10240	102000	79800

10. Secondary Outcome

Title	Persistence of AUTO3 Following Adoptive Transfer
Description	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).
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Patients who received at least 1 (complete or partial) dose of AUTO3 and had evaluable cellular kinetics data (who had at least 1 cellular kinetics concentration post AUTO3 infusion above the lower limit of quantitation) (cellular kinetics analysis set)

Arm/Group Title	1x10^6 CD19/CD22 CAR-positive T Cells/kg	3x10^6 CD19/CD22 CAR-positive T Cells/kg	5x10^6 CD19/CD22 CAR-positive T Cells/kg
Arm/Group Description	Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells	All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells	Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells
Measure Participants	4	5	4
Median (Full Range) [days]	41.7	343.7	24.3

11. Secondary Outcome

Title	Duration of B Cell Aplasia
Description	Depletion of circulating B cells assessed by flow cytometry at a range of time points in the peripheral blood
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Patients who received at least 1 (complete or partial) dose of the pre-conditioning regimen (safety set)

Arm/Group Title	1x10^6 CD19/CD22 CAR-positive T Cells/kg	3x10^6 CD19/CD22 CAR-positive T Cells/kg	5x10^6 CD19/CD22 CAR-positive T Cells/kg
Arm/Group Description	Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells	All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells	Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells
Measure Participants	4	5	6
Median (95% Confidence Interval) [months]	NA	NA	NA

Adverse Events

Time Frame	From AUTO3 infusion (Day 0) until the end of study (2 years after last patient dosed) or withdrawal, whichever occurred first
Arm/Group Title	1x10^6 CD19/CD22 CAR-positive T Cells/kg		3x10^6 CD19/CD22 CAR-positive T Cells/kg		5x10^6 CD19/CD22 CAR-positive T Cells/kg
Arm/Group Description	Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells		All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells		Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells
All Cause Mortality
	1x10^6 CD19/CD22 CAR-positive T Cells/kg		3x10^6 CD19/CD22 CAR-positive T Cells/kg		5x10^6 CD19/CD22 CAR-positive T Cells/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/4 (75%)		3/5 (60%)		3/6 (50%)
Serious Adverse Events
	1x10^6 CD19/CD22 CAR-positive T Cells/kg		3x10^6 CD19/CD22 CAR-positive T Cells/kg		5x10^6 CD19/CD22 CAR-positive T Cells/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/4 (25%)		2/5 (40%)		3/6 (50%)
Blood and lymphatic system disorders
Anaemia	0/4 (0%)	0	1/5 (20%)	1	2/6 (33.3%)	2
Febrile neutropenia	0/4 (0%)	0	1/5 (20%)	1	1/6 (16.7%)	1
Neutropenia	0/4 (0%)	0	1/5 (20%)	1	2/6 (33.3%)	2
Thrombocytopenia	0/4 (0%)	0	1/5 (20%)	1	2/6 (33.3%)	2
General disorders
Pyrexia	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1
Infections and infestations
Cellulitis	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1
Nervous system disorders
Encephalopathy	1/4 (25%)	1	0/5 (0%)	0	0/6 (0%)	0
Seizure	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1
Other (Not Including Serious) Adverse Events
	1x10^6 CD19/CD22 CAR-positive T Cells/kg		3x10^6 CD19/CD22 CAR-positive T Cells/kg		5x10^6 CD19/CD22 CAR-positive T Cells/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		5/5 (100%)		6/6 (100%)
Blood and lymphatic system disorders
Anaemia	0/4 (0%)	0	3/5 (60%)	5	1/6 (16.7%)	1
Febrile neutropenia	2/4 (50%)	2	2/5 (40%)	2	2/6 (33.3%)	2
Neutropenia	0/4 (0%)	0	1/5 (20%)	4	2/6 (33.3%)	4
Thrombocytopenia	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0
Cardiac disorders
Tachycardia	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1
Eye disorders
Vision blurred	1/4 (25%)	1	1/5 (20%)	1	0/6 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/4 (25%)	1	0/5 (0%)	0	1/6 (16.7%)	2
Abdominal pain upper	1/4 (25%)	1	0/5 (0%)	0	0/6 (0%)	0
Anal haemorrhage	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1
Diarrhoea	2/4 (50%)	2	1/5 (20%)	2	1/6 (16.7%)	1
Dyspepsia	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0
Gastrooesophageal reflux disease	1/4 (25%)	1	0/5 (0%)	0	0/6 (0%)	0
Haematochezia	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0
Lip dry	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1
Nausea	1/4 (25%)	1	2/5 (40%)	2	2/6 (33.3%)	2
Stomatitis	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0
Toothache	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0
Vomiting	1/4 (25%)	1	0/5 (0%)	0	4/6 (66.7%)	4
General disorders
Chills	1/4 (25%)	1	1/5 (20%)	1	0/6 (0%)	0
Fatigue	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0
Pyrexia	1/4 (25%)	6	3/5 (60%)	9	5/6 (83.3%)	16
Infections and infestations
Catheter bacteraemia	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1
Device related infection	1/4 (25%)	2	0/5 (0%)	0	0/6 (0%)	0
Enterococcal infection	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1
Folliculitis	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1
Gingival abscess	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1
Infectious pleural effusion	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0
Parvovirus infection	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0
Staphylococcal infection	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0
Upper respiratory tract infection	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0
Injury, poisoning and procedural complications
Infusion related reaction	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0
Limb injury	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1
Procedural pain	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1
Soft tissue injury	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1
Investigations
Blood bilirubin increased	1/4 (25%)	2	0/5 (0%)	0	0/6 (0%)	0
Human herpes virus 6 serology positive	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0
Lymphocyte count decreased	0/4 (0%)	0	0/5 (0%)	0	2/6 (33.3%)	4
Neutrophil count decreased	2/4 (50%)	2	2/5 (40%)	24	1/6 (16.7%)	2
Platelet count decreased	0/4 (0%)	0	0/5 (0%)	0	2/6 (33.3%)	6
Staphylococcus test positive	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1
Metabolism and nutrition disorders
Decreased appetite	0/4 (0%)	0	3/5 (60%)	4	2/6 (33.3%)	2
Gout	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1
Hypokalaemia	0/4 (0%)	0	1/5 (20%)	1	1/6 (16.7%)	2
Hypophosphataemia	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1
Musculoskeletal and connective tissue disorders
Neck pain	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0
Pain in extremity	0/4 (0%)	0	2/5 (40%)	2	3/6 (50%)	3
Nervous system disorders
Aphasia	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0
Dizziness	1/4 (25%)	1	0/5 (0%)	0	2/6 (33.3%)	2
Headache	1/4 (25%)	1	2/5 (40%)	2	1/6 (16.7%)	1
Paraesthesia	2/4 (50%)	2	1/5 (20%)	1	0/6 (0%)	0
Peripheral sensory neuropathy	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0
Syncope	1/4 (25%)	1	0/5 (0%)	0	0/6 (0%)	0
Psychiatric disorders
Hallucination	1/4 (25%)	1	0/5 (0%)	0	0/6 (0%)	0
Renal and urinary disorders
Dysuria	1/4 (25%)	1	0/5 (0%)	0	0/6 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1
Dyspnoea	1/4 (25%)	1	0/5 (0%)	0	0/6 (0%)	0
Epistaxis	0/4 (0%)	0	1/5 (20%)	1	1/6 (16.7%)	1
Hypoxia	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0
Painful respiration	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1
Pleural effusion	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0
Skin and subcutaneous tissue disorders
Erythema multiforme	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0
Pruritus	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1
Rash	0/4 (0%)	0	0/5 (0%)	0	1/6 (16.7%)	1
Rash erythematous	1/4 (25%)	1	0/5 (0%)	0	0/6 (0%)	0
Rash maculo-papular	0/4 (0%)	0	1/5 (20%)	1	1/6 (16.7%)	1
Rash papular	1/4 (25%)	1	0/5 (0%)	0	0/6 (0%)	0
Vascular disorders
Hypertension	1/4 (25%)	1	0/5 (0%)	0	0/6 (0%)	0
Hypotension	0/4 (0%)	0	1/5 (20%)	1	0/6 (0%)	0

Limitations/Caveats

Early completion of the study leading to small numbers of patients analyzed from the Phase I part of the study.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.