CARPALL: Immunotherapy With CD19/22 CAR T-cells for CD19+ Haematological Malignancies

Study Overview
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Brief Summary
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This study aims to evaluate the safety, efficacy and duration of response of CD19/22 Chimeric Antigen Receptor (CAR) redirected autologous T-cells in children with high risk, relapsed CD19+ and/ or CD22+ haematological malignancies.

Detailed Description
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This is a multi-centre, non-randomised, open label Phase I clinical trial of an Advanced Therapy Investigational Medicinal Product named CD19/22 Chimeric Antigen Receptor (CAR) T-cells (CD19/22 CAR T-cells) in children and young adults (age <24 years) with high risk, relapsed CD19+ and/or CD1922+ haematological malignancies (Acute Lymphoblastic Leukemia and Burkitt's lymphoma). Following informed consent and registration to the trial, patients will undergo an unstimulated leukapheresis for the generation of the CD19/22 CAR T-cells. Patients will receive the CD19/22CAR T-cells following lymphodepleting chemotherapy. The study will evaluate the safety, efficacy and duration of response of the CD19/22 CAR T-cells in children with high risk relapsed CD19+ and or CD22+ malignancies.

Official Title
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Immunotherapy With CD19/22 CAR Redirected T-cells for High Risk, Relapsed Paediatric CD19+ and/or CD22+ Acute Lymphoblastic Leukaemia and Other Haematological Malignancies

Conditions
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Acute Lymphoblastic Leukemia, Burkitt Lymphoma

Intervention / Treatment
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* Procedure: Leukapheresis
* Drug: Lymphodepletion with fludarabine
* Drug: Lymphodepletion with cyclophosphamide
* Biological: CD19/22 CAR T-cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children and young adults (age 24 years or younger) with high risk/relapsed CD19+ and / or CD22+ haematological malignancy: A) Resistant disease (>5% blasts) at end of UKALL 2019 guidelines or equivalent induction B) ALL with persisting high level MRD at 2nd time point of frontline national protocol (currently MRD >10-4 at week 14 UKALL2019 guidelines or equivalent). C) High risk infant ALL (age < 6 months at diagnosis with MLL gene rearrangement and either presenting white cell count > 300 x 109/L or poor steroid early response (i.e. circulating blast count >1x109/L following 7 day steroid pre-phase of induction as per national guidelines or equivalent) D) Intermediate risk infant ALL with MRD > 10-3 at end of induction following national guidelines or equivalent) E) High risk 1st relapse (as defined by updated IntreALL 2019 classification: bone marrow or combined relapse within 30 months of diagnosis OR any relapse within 18 months of diagnosis) F) Standard risk relapse in patients with high risk cytogenetics (defined as BCR-ABL, KMT2A rearrangement, near-haploidy (<30 chromosomes) and low hypodiploidy (30-39 chromosomes), iAMP21 and TCF3-HLF translocations). G) Standard risk relapse with bone marrow minimal residual disease (MRD) > 10-3 at end of re-induction H) Any on therapy relapse in patients age 16-24 I) Any relapse of infant ALL J) ALL post ≥ 2nd relapse K) Any refractory relapse of ALL (defined as > 1% blasts by flow cytometry after a at least 1 cycle of standard chemotherapy) L) ALL with MRD >10-4 prior to planned stem cell transplant M) Any relapse of ALL eligible for stem cell transplant but no available HLA matched donor or other contraindication to transplant N) Any relapse of ALL after stem cell transplant O) Any relapse of Burkitt's or other CD19+ and/or CD22+lymphoma Note patients with isolated CNS relapse meeting one or more of the criteria above are eligible for the study Agreement to have a pregnancy test, use adequate contraception (if applicable) Written informed consent Exclusion Criteria: Exclusion Criteria for registration: Active Hepatitis B, C or HIV infection Oxygen saturation ≤ 90% on air Bilirubin > 3 x upper limit of normal Creatinine > 3 x upper limit of normal Women who are pregnant or breastfeeding Stem Cell Transplant patients only: active significant (overall Grade ≥ II, Seattle criteria) acute GVHD or moderate/ severe chronic GVHD (NIH consensus criteria) requiring systemic steroids. Inability to tolerate leucapheresis Karnofsky (age ≥ 10 years) or Lansky (age < 10) score ≤ 50% Pre-existing significant neurological disorder (other than CNS involvement of underlying haematological malignancy) Exclusion criteria for CD19/22CAR T-cell infusion: Severe intercurrent infection at the time of scheduled CD19/22 CAR T-cell infusion Requirement for supplementary oxygen or active pulmonary infiltrates at the time of scheduled CD19/22 CAR T-cell infusion Allogeneic transplant recipients with active significant acute GVHD overall grade ≥II or moderate/severe chronic GVHD requiring systemic steroids at the time of scheduled CD19/22 CAR T-cell infusion. Note: Such patients will be excluded until the patient is GVHD free and off steroids

Ages Eligible for Study
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Maximum Age: 24 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CD19/22 CAR T-cells<br>Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19/22CAR T-cells. Patients will receive lymphodepletion with fludarabine and cyclophosphamide prior to infusion of the CD19/22CAR T-cells. | Procedure: Leukapheresis<br>* Patients will undergo an unstimulated leukapheresis to isolate the required immune cells to produce the CD19/22 CAR T-cells<br>Drug: Lymphodepletion with fludarabine<br>* Patients will receive lymphodepleting chemotherapy with iv fludarabine 30 mg/m2 on days -7 to -3 prior to CD19/22CAR T-cell infusion.<br>Drug: Lymphodepletion with cyclophosphamide<br>* Patients will receive lymphodepleting chemotherapy with iv cyclophosphamide 0.5 g/m2 on days -4 to -2 prior to CD19/22CAR T-cell infusion.<br>Biological: CD19/22 CAR T-cells<br>* A single dose of 1 x 10^6/kg CD19/22CAR transduced T-cells will be given as an intravenous injection through a Hickman line or PICC line(peripherally inserted central catheter) on day 0.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity evaluation following CD19/22CAR T-cell infusion | The incidence of grade 3-5 toxicity occurring within 60 days of CD19/22CAR T-cell infusion. In particular, the incidence of Severe Cytokine Release Syndrome and Grade 3-5 neurotoxicity occurring within 30 days of CD19/22CAR T-cell infusion. | 1 month | 
| Molecular remission | 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 1 month post CD19/22CAR T-cell infusion will be determined. | 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Long term molecular remission | Number of patients in molecular remission without further therapy at 2 years | 2 years | 
| Frequency of circulating CD19/22 CAR T-cells | Persistence and frequency of circulating CD19/22CAR T-cells in the peripheral blood by flow cytometry and qPCR analyses. | 2 years | 
| Incidence of hypogammaglobulinaemia | Incidence and duration of hypogammaglobulinaemia | 2 years | 
| Relapse rate | Relapse rate monitored during interventional phase and long term follow up for a total of10 years post cell infusion. Number of patients who relapsed can be summarized as a percentage or rate(for all patients registered to the trial, and also only for those who received the cell infusion). | 10 years | 
| Overall Survival | Overall survival is monitored during interventional phase and long term follow up for 10 years post-CD19/22 CAR T-cell infusion. Number of patients alive can be summarized as a percentage (for all patients registered to the trial, and also only for those who received the cell infusion). | 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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high risk relapsed CD19+ and/or CD22+ hematological malignancies