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

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.

Inclusion criteria

• Children and young adults (age 24 years or younger) with high risk/relapsed CD19+ and CD22+ acute lymphoblastic leukaemia with:

• Resistant disease (>5% blasts) at end of ALLTogether-1 protocol or equivalent induction
• 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).
• 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)
• Any patient with t(17,19) TCF3-HLF rearrangement
• 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
• Any on therapy relapse in patients age 16-24
• Any relapse of infant ALL
• ALL post ≥ 2nd relapse
• Any refractory relapse of ALL (defined as > 1% blasts by flow cytometry after a at least 1 cycle of standard chemotherapy)
• ALL with MRD >10-4 prior to planned stem cell transplant
• Any relapse of ALL eligible for stem cell transplant but no available HLA matched donor or other contraindication to transplant
• Any relapse of ALL after stem cell transplant as long as planned time of CD19+CD22CAR T cell infusion is > 4 months post-transplant
• 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

• 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)
• CD19 negative or CD22 negative disease

Exclusion criteria

for CD19+CD22CAR T-cell infusion:

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