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CD19 /22 CAR T Cells (AUTO3) for the Treatment of B Cell Acute Lymphoblastic Leukemia (ALL)
Phase 1, PHASE2 trial testing AUTO3 (CD19/22 CAR T cells in B Acute Lymphoblastic Leukemia in 23 participants. Completed in 18 May 2020.
| Lead sponsor | Autolus Limited |
|---|---|
| Phase | Phase 1, PHASE2 |
| Status | Completed |
| Study type | INTERVENTIONAL |
| Allocation | na |
| Design | single group |
| Masking | none |
| Primary purpose | treatment |
| Enrollment | 23 |
| Start date | 26 June 2017 |
| Primary completion | 18 May 2020 |
| Estimated completion | 18 May 2020 |
| Sites | 3 locations across United Kingdom |
Autolus Limited — full company profile →
Adults 1 to 24, any sex, with B Acute Lymphoblastic Leukemia or Recurrent Childhood Acute Lymphoblastic Leukemia. Patients with the condition only — healthy volunteers not accepted.
Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.
| Group | Value | 95% CI |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | 4 | |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg | 4 | |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg | 6 |
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
| Group | Value | 95% CI |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | 0 | |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg | 0 | |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg | 0 |
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.
| Group | Value | 95% CI |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | 3 | |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg | 5 | |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg | 5 |
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).
| Group | Value | 95% CI |
|---|---|---|
| AUTO3 | 19 |
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.
| Group | Value | 95% CI |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | 3.48 | 0.03 – NA |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg | 12.42 | 3.94 – NA |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg | 2.79 | 0.03 – NA |
| Group | Value | 95% CI |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | 0 | |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg | 2 | |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg | 1 |
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.
| Group | Value | 95% CI |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | 6.09 | 2.56 – NA |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg | 11.50 | 3.02 – NA |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg | 3.98 | 1.87 – NA |
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.
| Group | Value | 95% CI |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | 10.17 | 2.30 – NA |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg | 25.20 | 4.34 – NA |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg | NA | 4.07 – NA |
Expansion of AUTO3 was measured as the median peak (Cmax) of transgene levels in the peripheral blood after AUTO3 infusion
| Group | Value | 95% CI |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | 10240 | 5690 – 37000 |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg | 102000 | 34800 – 127000 |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg | 79800 | 13200 – 104000 |
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).
| Group | Value | 95% CI |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | 41.7 | 19.8 – 256.8 |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg | 343.7 | 62.7 – 538.9 |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg | 24.3 | 18.8 – 570.8 |
Depletion of circulating B cells assessed by flow cytometry at a range of time points in the peripheral blood
| Group | Value | 95% CI |
|---|---|---|
| 1x10^6 CD19/CD22 CAR-positive T Cells/kg | NA | NA – NA |
| 3x10^6 CD19/CD22 CAR-positive T Cells/kg | NA | NA – NA |
| 5x10^6 CD19/CD22 CAR-positive T Cells/kg | NA | NA – NA |
Time frame: From AUTO3 infusion (Day 0) until the end of study (2 years after last patient dosed) or withdrawal, whichever occurred first. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.
| Reaction | System | 1x10^6 CD19/CD22 CAR-posit… | 3x10^6 CD19/CD22 CAR-posit… | 5x10^6 CD19/CD22 CAR-posit… |
|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | — | — | — |
| Neutropenia | Blood and lymphatic system disorders | — | — | — |
| Thrombocytopenia | Blood and lymphatic system disorders | — | — | — |
| Febrile neutropenia | Blood and lymphatic system disorders | — | — | — |
| Pyrexia | General disorders | — | — | — |
| Cellulitis | Infections and infestations | — | — | — |
| Encephalopathy | Nervous system disorders | — | — | — |
| Seizure | Nervous system disorders | — | — | — |
| Reaction | System | 1x10^6 CD19/CD22 CAR-posit… | 3x10^6 CD19/CD22 CAR-posit… | 5x10^6 CD19/CD22 CAR-posit… |
|---|---|---|---|---|
| Pyrexia | General disorders | — | — | — |
| Vomiting | Gastrointestinal disorders | — | — | — |
| Anaemia | Blood and lymphatic system disorders | — | — | — |
| Decreased appetite | Metabolism and nutrition disorders | — | — | — |
| Pain in extremity | Musculoskeletal and connective tissue disorders | — | — | — |
| Febrile neutropenia | Blood and lymphatic system disorders | — | — | — |
| Neutropenia | Blood and lymphatic system disorders | — | — | — |
| Diarrhoea | Gastrointestinal disorders | — | — | — |
| Nausea | Gastrointestinal disorders | — | — | — |
| Lymphocyte count decreased | Investigations | — | — | — |
| Neutrophil count decreased | Investigations | — | — | — |
| Platelet count decreased | Investigations | — | — | — |
| Dizziness | Nervous system disorders | — | — | — |
| Headache | Nervous system disorders | — | — | — |
| Paraesthesia | Nervous system disorders | — | — | — |
| Thrombocytopenia | Blood and lymphatic system disorders | — | — | — |
| Tachycardia | Cardiac disorders | — | — | — |
| Vision blurred | Eye disorders | — | — | — |
| Abdominal pain | Gastrointestinal disorders | — | — | — |
| Abdominal pain upper | Gastrointestinal disorders | — | — | — |
| Anal haemorrhage | Gastrointestinal disorders | — | — | — |
| Dyspepsia | Gastrointestinal disorders | — | — | — |
| Gastrooesophageal reflux disease | Gastrointestinal disorders | — | — | — |
| Haematochezia | Gastrointestinal disorders | — | — | — |
| Lip dry | Gastrointestinal disorders | — | — | — |
| Stomatitis | Gastrointestinal disorders | — | — | — |
| Toothache | Gastrointestinal disorders | — | — | — |
| Chills | General disorders | — | — | — |
| Fatigue | General disorders | — | — | — |
| Catheter bacteraemia | Infections and infestations | — | — | — |
| Device related infection | Infections and infestations | — | — | — |
| Enterococcal infection | Infections and infestations | — | — | — |
| Folliculitis | Infections and infestations | — | — | — |
| Gingival abscess | Infections and infestations | — | — | — |
| Infectious pleural effusion | Infections and infestations | — | — | — |
| Parvovirus infection | Infections and infestations | — | — | — |
| Staphylococcal infection | Infections and infestations | — | — | — |
| Upper respiratory tract infection | Infections and infestations | — | — | — |
| Infusion related reaction | Injury, poisoning and procedural complications | — | — | — |
| Limb injury | Injury, poisoning and procedural complications | — | — | — |
Most-reported serious reactions: Anaemia, Neutropenia, Thrombocytopenia, Febrile neutropenia, Pyrexia, Cellulitis, Encephalopathy, Seizure.
Data from ClinicalTrials.gov NCT03289455 adverse events section.
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.
8 peer-reviewed publications reference this trial (live from Europe PMC):
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