CARPALL: Immunotherapy with CD19+CD22 CAR T-cells for CD19+ and CD22+ Acute Lymphoblastic Leukaemia

Phase 1

Recruiting

• Conditions: Acute Lymphoblastic Leukemia
• Interventions: Procedure: Leukapheresis; Radiation: Total Body Irradiation (TBI); Drug: Lymphodepletion with Fludarabine; Drug: Lymphodepletion with Cyclophosphamide; Biological: CD19+CD22 CAR T-cells

• Registration Number: NCT02443831
• Lead Sponsor: University College, London

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.

Study Timeline

• Study First Submitted: 2015-04-29
• Study First Submitted QC: 2015-05-13
• Study First Posted: 2015-05-14
• Study Start: 2016-04
• Status Verified: 2025-02
• Last Update Submitted: 2025-03-26
• Last Update Posted: 2025-04-02
• Primary Completion: 2026-12-31
• Study Completion: 2041-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 50

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

Exclusion Criteria

Exclusion Criteria for registration:

1. Active Hepatitis B, C or HIV infection
2. Oxygen saturation ≤ 90% on air
3. Bilirubin > 3 x upper limit of normal
4. Creatinine > 3 x upper limit of normal
5. Women who are pregnant or breastfeeding
6. 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.
7. Inability to tolerate leucapheresis
8. Karnofsky (age ≥ 10 years) or Lansky (age < 10) score ≤ 50%
9. Pre-existing significant neurological disorder (other than CNS involvement of underlying haematological malignancy)
10. CD19 negative or CD22 negative disease

Exclusion criteria for CD19+CD22CAR T-cell infusion:

1. Severe intercurrent infection at the time of scheduled CD19+CD22 CAR T-cell infusion
2. Requirement for supplementary oxygen or active pulmonary infiltrates at the time of scheduled CD19+CD22 CAR T-cell infusion
3. 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+CD22 CAR T-cell infusion. Note: Such patients will be excluded until the patient is GVHD free and off steroids

In addition, for CAR T infusion on D14: absence of CRS>Gr2 or ICANS>Gr2 after D0 CAR T infusion.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
CD19+CD22 CAR T-cells	Leukapheresis	Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19+CD22CAR T-cells. Patients will receive lymphodepletion with low dose total body irradiation, fludarabine and cyclophosphamide prior to infusion of the CD19+CD22CAR T-cells.
CD19+CD22 CAR T-cells	Total Body Irradiation (TBI)	Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19+CD22CAR T-cells. Patients will receive lymphodepletion with low dose total body irradiation, fludarabine and cyclophosphamide prior to infusion of the CD19+CD22CAR T-cells.
CD19+CD22 CAR T-cells	Lymphodepletion with Fludarabine	Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19+CD22CAR T-cells. Patients will receive lymphodepletion with low dose total body irradiation, fludarabine and cyclophosphamide prior to infusion of the CD19+CD22CAR T-cells.
CD19+CD22 CAR T-cells	Lymphodepletion with Cyclophosphamide	Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19+CD22CAR T-cells. Patients will receive lymphodepletion with low dose total body irradiation, fludarabine and cyclophosphamide prior to infusion of the CD19+CD22CAR T-cells.
CD19+CD22 CAR T-cells	CD19+CD22 CAR T-cells	Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19+CD22CAR T-cells. Patients will receive lymphodepletion with low dose total body irradiation, fludarabine and cyclophosphamide prior to infusion of the CD19+CD22CAR T-cells.

Primary Outcome Measures

Name	Time	Method
Incidence of dose limiting toxicity (DLT) following CD19+CD22 CAR T-cell infusion	28 days	The incidence of dose limiting toxicity (DLT) 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 Outcome Measures

Name	Time	Method
Incidence of Hypogammaglobulinaemia	2 years	Incidence of hypogammaglobulinaemia
Feasibility of Generation of CD19+CD22 CAR T-cells	Day 28	Evaluated by the number of therapeutic products generated.
Long-Term Molecular Remission	2 years	Number of patients in molecular remission without further therapy at 1 and 2 years
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.
Incidence of B Aplasia	2 years	Incidence of B aplasia
Relapse rate	2 years	Relapse rate
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.
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.
Safety and Tolerability of the CAR T-cells	15 years	Incidence of adverse events and reactions (toxicity) to the CAR T-cells.
Overall Survival (OS)	2 years	Overall Survival (OS) at 1 and 2 years

Trial Locations

Locations (3)

Great Ormond Street Hospital; 🇬🇧 London, United Kingdom

University College Hospital; 🇬🇧 London, United Kingdom

Manchester Royal Children's Hospital; 🇬🇧 Manchester, United Kingdom