B Acute Lymphoblastic Leukemia, B-cell Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Lymphoblastic Leukemia, Refractory Childhood Acute Lymphoblastic Leukemia
Conditions
Keywords
Acute Lymphoblastic Leukaemia, CD19 Positive, CD22 Positive, Relapsed Acute Lymphoblastic Leukaemia, Refractory Acute Lymphoblastic Leukaemia, AUTO3
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.
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.
Interventions
BIOLOGICALAUTO3 (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.
Sponsors
Autolus Limited
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 24 Years
Healthy volunteers
No
Inclusion criteria
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:) 7. Primary refractory disease; OR, 8. 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, 9. Isolated CNS relapse but with ≤CNS Grade 2 disease at time of enrolment. 2. Documentation of CD19 and or CD22 expression on leukaemic blasts in the BM, peripheral blood, or cerebrospinal fluid within 3 months of screening. 3. Detectable disease in the BM at a level ≥10-⁴ (Phase I only). 4. Absolute lymphocyte count ≥0.5 x 10⁹/L. 5. Adequate renal, hepatic, pulmonary, and cardiac function. 6. Karnofsky (age ≥10 years) or Lansky (age \<10 years) score ≥50%. 7. 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: 1. 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. 2. Allogeneic cellular therapy: Any donor lymphocyte infusions must be completed \>6 weeks prior to AUTO3 infusion. 3. Graft versus host disease therapies: Any drug used for GVHD must be stopped \>4 weeks prior to AUTO3 infusion. 4. Chemotherapy: Should be stopped 1 week prior to leukapheresis and 2 days prior to starting pre-conditioning chemotherapy. 11. Known allergy to albumin, dimethyl sulfoxide, cyclophosphamide or fludarabine. For AUTO3 Infusion: Patients meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | — |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| Number of Patients With CD19- and/or CD22-negative Relapse | Up to 2 years | — |
| 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 |
| 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). |
| 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 |
| 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). |
| 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. |
Countries
United Kingdom
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg Patients assigned in this Cohort received actual doses of 0.3 to 2x10\^6 CD19/CD22 CAR-positive T cells | 4 |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg All patients assigned in this Cohort received actual doses of 3x10\^6 CD19/CD22 CAR-positive T cells | 5 |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg Patients assigned in this Cohort received actual doses of 4.3 to 5x10\^6 CD19/CD22 CAR-positive T cells | 6 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 1 | 0 | 0 |
| Overall Study | No CART persistence in MRD negativity. Patient proceeded with HSCT | 0 | 0 | 1 |
| Overall Study | Progressive disease | 3 | 4 | 5 |
| Overall Study | Sponsor decision due to covid19 restrictions | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | 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 |
|---|---|---|---|---|
| Age, Categorical <=18 years | 15 Participants | 4 Participants | 5 Participants | 6 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Karnofsky/Lansky score | 90 percentage | 95 percentage | 90 percentage | 100 percentage |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 3 Participants | 5 Participants | 6 Participants |
| Region of Enrollment United Kingdom | 15 participants | 4 participants | 5 participants | 6 participants |
| Sex: Female, Male Female | 4 Participants | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 11 Participants | 4 Participants | 3 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 4 | 3 / 5 | 3 / 6 |
| other Total, other adverse events | 4 / 4 | 5 / 5 | 6 / 6 |
| serious Total, serious adverse events | 1 / 4 | 2 / 5 | 3 / 6 |
Outcome results
Primary
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.
Time frame: Within 30 days (+/- 3 days) post AUTO3 infusion
Population: Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | 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)). | 3 Participants |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg | 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)). | 5 Participants |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg | 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)). | 5 Participants |
Primary
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.
Time frame: Within 30 days (+/- 3 days) after the last dose of AUTO3.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | Number of Patients With Dose Limiting Toxicity (DLT) of AUTO3 | 0 Participants |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg | Number of Patients With Dose Limiting Toxicity (DLT) of AUTO3 | 0 Participants |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg | Number of Patients With Dose Limiting Toxicity (DLT) of AUTO3 | 0 Participants |
Primary
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.
Population: Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | Number of Patients With Grade 3-5 Toxicities Occurring Within the Dose Limiting Toxicity (DLT) Period of AUTO3 Infusion | 4 Participants |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg | Number of Patients With Grade 3-5 Toxicities Occurring Within the Dose Limiting Toxicity (DLT) Period of AUTO3 Infusion | 4 Participants |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg | Number of Patients With Grade 3-5 Toxicities Occurring Within the Dose Limiting Toxicity (DLT) Period of AUTO3 Infusion | 6 Participants |
Secondary
Duration of B Cell Aplasia
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
Population: Patients who received at least 1 (complete or partial) dose of the pre-conditioning regimen (safety set)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | Duration of B Cell Aplasia | NA months |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg | Duration of B Cell Aplasia | NA months |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg | Duration of B Cell Aplasia | NA months |
Secondary
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.
Time frame: Up to 2 years
Population: Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | Event-Free Survival (EFS) by Morphological Analysis | 3.48 months |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg | Event-Free Survival (EFS) by Morphological Analysis | 12.42 months |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg | Event-Free Survival (EFS) by Morphological Analysis | 2.79 months |
Secondary
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
Time frame: Up to 2 years
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | Expansion of AUTO3 Following Adoptive Transfer | 10240 vector copies/ug DNA |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg | Expansion of AUTO3 Following Adoptive Transfer | 102000 vector copies/ug DNA |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg | Expansion of AUTO3 Following Adoptive Transfer | 79800 vector copies/ug DNA |
Secondary
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).
Time frame: Up to 8 weeks post leukapheresis
Population: Patients who underwent leukapheresis. This outcome is measured before patients received infusion with AUTO3. Therefore, no split by dose cohort can be provided.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | Feasibility of Generating AUTO3: Number of Patients' Cells Successfully Manufactured as a Proportion of the Number of Patients Undergoing Leukapheresis | 19 Participants |
Secondary
Number of Patients With CD19- and/or CD22-negative Relapse
Time frame: Up to 2 years
Population: Patients who received at least 1 (complete or partial dose) of AUTO3 and had morphological relapses
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | Number of Patients With CD19- and/or CD22-negative Relapse | 0 Participants |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg | Number of Patients With CD19- and/or CD22-negative Relapse | 2 Participants |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg | Number of Patients With CD19- and/or CD22-negative Relapse | 1 Participants |
Secondary
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.
Time frame: Up to 2 years after the last patient was infused
Population: Patients who received at least 1 (complete or partial) dose of AUTO3
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | Overall Survival (OS) | 10.17 months |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg | Overall Survival (OS) | 25.20 months |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg | Overall Survival (OS) | NA months |
Secondary
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).
Time frame: Up to 2 years
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | Persistence of AUTO3 Following Adoptive Transfer | 41.7 days |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg | Persistence of AUTO3 Following Adoptive Transfer | 343.7 days |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg | Persistence of AUTO3 Following Adoptive Transfer | 24.3 days |
Secondary
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.
Time frame: Up to 2 years
Population: Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | Relapse-Free Survival (RFS) by Morphological Analysis | 6.09 months |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg | Relapse-Free Survival (RFS) by Morphological Analysis | 11.50 months |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg | Relapse-Free Survival (RFS) by Morphological Analysis | 3.98 months |