Acute Lymphoblastic Leukemia
Conditions
Keywords
high risk relapsed CD19+ and CD22+ acute lymphoblastic leukaemia
Brief summary
This study aims to evaluate the safety, efficacy and duration of response of CD19+CD22 Chimeric Antigen Receptor (CAR) redirected autologous T-cells in children with high risk, relapsed CD19+ and CD22+ acute lymphoblastic leukaemia
Detailed description
This is a multi-centre, non-randomised, open label Phase I clinical trial of an Advanced Therapy Investigational Medicinal Product named CD19+CD22 Chimeric Antigen Receptor (CAR) T-cells (CD19+CD22 CAR T-cells) in children and young adults (age \<24 years) with high risk, relapsed CD19+ and CD22+ acute lymphoblastic leukaemia. Following informed consent and registration to the trial, patients will undergo an unstimulated leukapheresis for the generation of the CD19+CD22 CAR T-cells. Patients will receive the CD19+CD22CAR T-cells following lymphodepleting chemotherapy and total body irradiation. The study will evaluate the safety, efficacy and duration of response of the CD19+CD22 CAR T-cells in children with high risk relapsed CD19+ and CD22+ acute lymphoblastic leukaemia.
Interventions
DRUGLymphodepletion with Cyclophosphamide
Patients will receive lymphodepleting chemotherapy with iv cyclophosphamide on days -6 to -5 prior to CD19+CD22CAR T-cell infusion.
PROCEDURELeukapheresis
Patients will undergo an unstimulated leukapheresis to isolate the required immune cells to produce the CD19+CD22 CAR T-cells
RADIATIONTotal Body Irradiation (TBI)
Participants will receive low-dose total body irradiation delivered as a single fraction on day -7 prior to CD19+CD22CAR T-cell infusion.
DRUGLymphodepletion with Fludarabine
Patients will receive lymphodepleting chemotherapy with iv fludarabine on days -6 to -3 prior to CD19+CD22CAR T-cell infusion.
BIOLOGICALCD19+CD22 CAR T-cells
1 dose of CD19+CD22 CAR T-cells given as an intravenous injection through a Hickman line or PICC line (peripherally inserted central catheter) on day 0.
Sponsors
University College, London
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 24 Years
Healthy volunteers
No
Inclusion criteria
1. Children and young adults (age 24 years or younger) with high risk/relapsed CD19+ and CD22+ acute lymphoblastic leukaemia with: 1. Resistant disease (\>5% blasts) at end of ALLTogether-1 protocol or equivalent induction 2. ALL with persisting high level MRD at 2nd time point of frontline national protocol (currently MRD \>10-4 at week 9 ALLTogether-1 Protocol or equivalent). 3. High risk infant ALL (age \< 6 months at diagnosis with MLL gene rearrangement and either presenting white cell count \> 300 x 10\^9/L or poor steroid early response (i.e. circulating blast count \>1x10\^9/L following 7 day steroid pre-phase of induction as per national guidelines or equivalent) 4. Any patient with t(17,19) TCF3-HLF rearrangement 5. High risk 1st relapse (defined as very early (relapse within 18 months of diagnosis) and early relapses (any patient relapsing on therapy or within 6 months of completing treatment) and any relapse with high risk genetics, namely (KMT2A (MLL) rearrangements, low hypodiploidy/near haploidy, t(17;19)(q22;p13)/TCF3-HLF, iAMP21 and t(1;19)(q21;p13)/TCF3- PBX1, t(9;22)(34.1 q11.2)/BCR-ABL1 6. Any on therapy relapse in patients age 16-24 7. Any relapse of infant ALL 8. ALL post ≥ 2nd relapse 9. Any refractory relapse of ALL (defined as \> 1% blasts by flow cytometry after a at least 1 cycle of standard chemotherapy) 10. ALL with MRD \>10-4 prior to planned stem cell transplant 11. Any relapse of ALL eligible for stem cell transplant but no available HLA matched donor or other contraindication to transplant 12. Any relapse of ALL after stem cell transplant as long as planned time of CD19+CD22CAR T cell infusion is \> 4 months post-transplant 13. Early (defined as \< 6 months post-infusion) loss of B cell aplasia or any CD19+CD22+ relapse following CD19CAR T cell therapy with Tisagenlecleucel Note patients with isolated CNS relapse meeting one or more of the criteria above are eligible for the study 2. Agreement to have a pregnancy test, use adequate contraception (if applicable) 3. Written informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of unacceptable toxicity following CD19+CD22 CAR T-cell infusion | 28 days | The incidence of unacceptable toxicity occurring within 28 days of CD19+CD22CAR T-cell infusion. |
| Molecular remission | 28 days | Efficacy will be assessed by determining Minimal Residual Disease in the bone marrow aspirate using immunoglobulin heavy chain (IgH) quantitative polymerase chain reaction (qPCR) and/or Next Generation Sequencing in all patients. The proportion of patients achieving molecular remission at 28 days post CD19+CD22CAR T-cell infusion will be determined. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility of Generation of CD19+CD22 CAR T-cells | Day 28 | Evaluated by the number of therapeutic products generated. |
| Molecular Remission | 3 months | Efficacy will be assessed by determining Minimal Residual Disease in the bone marrow aspirate using immunoglobulin heavy chain (IgH) quantitative polymerase chain reaction (qPCR) and/or Next Generation Sequencing in all patients. The proportion of patients achieving molecular remission at 3 months post CD19+CD22CAR T-cell infusion will be determined. |
| Long-Term Molecular Remission | 2 years | Number of patients in molecular remission without further therapy at 1 and 2 years |
| Duration of Response | 15 years | Duration of response is measured from the time of achieving molecular remission or flow MRD negativity until the disease relapse or death, whichever occurs first. |
| Safety and Tolerability of the CAR T-cells | 15 years | Incidence of adverse events and reactions (toxicity) to the CAR T-cells. |
| Incidence of B Aplasia | 2 years | Incidence of B aplasia |
| Incidence of Hypogammaglobulinaemia | 2 years | Incidence of hypogammaglobulinaemia |
| Frequency of Circulating CD19+CD22 CAR T-cells | 2 years | Persistence and frequency of circulating CD19+CD22CAR T-cells in the peripheral blood by flow cytometry and qPCR analyses. |
| Relapse rate | 2 years | Relapse rate |
| Overall Survival (OS) | 2 years | Overall Survival (OS) at 1 and 2 years |
Countries
United Kingdom
Contacts
CONTACTAniqa Tasnim
STUDY_CHAIRPersis Amrolia
UCL Institute of Child Health
Outcome results
None listed