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

Official title

Immunotherapy With CD19+CD22 CAR Redirected T-cells for High Risk/Relapsed Paediatric CD19+ and CD22+ Acute Lymphoblastic Leukaemia

Overview

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

• Procedure Leukapheresis
  Patients will undergo an unstimulated leukapheresis to isolate the required immune cells to produce the CD19+CD22 CAR T-cells
• Radiation Total 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.
• Drug Lymphodepletion with Fludarabine
  Patients will receive lymphodepleting chemotherapy with iv fludarabine on days -6 to -3 prior to CD19+CD22CAR T-cell infusion.
• Drug Lymphodepletion with Cyclophosphamide
  Patients will receive lymphodepleting chemotherapy with iv cyclophosphamide on days -6 to -5 prior to CD19+CD22CAR T-cell infusion.
• Biological CD19+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.

Primary outcome measures

• Incidence of unacceptable toxicity following CD19+CD22 CAR T-cell infusion [Time frame: 28 days]
• Molecular remission [Time frame: 28 days]

Secondary outcome measures (10)

• Feasibility of Generation of CD19+CD22 CAR T-cells [Time frame: Day 28]
• Molecular Remission [Time frame: 3 months]
• Long-Term Molecular Remission [Time frame: 2 years]
• Duration of Response [Time frame: 15 years]
• Safety and Tolerability of the CAR T-cells [Time frame: 15 years]
• Incidence of B Aplasia [Time frame: 2 years]
• Incidence of Hypogammaglobulinaemia [Time frame: 2 years]
• Frequency of Circulating CD19+CD22 CAR T-cells [Time frame: 2 years]
• Relapse rate [Time frame: 2 years]
• Overall Survival (OS) [Time frame: 2 years]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United Kingdom · 3 centers

• Great Ormond Street Hospital — London
• University College Hospital — London
• Manchester Royal Children's Hospital — Manchester

Publications

• Ghorashian S, Lucchini G, Richardson R, Nguyen K, Terris C, Guvenel A, Oporto-Espuelas M, Yeung J, Pinner D, Chu J, Williams L, Ko KY, Walding C, Watts K, Inglott S, Thomas R, Connor C, Adams S, Gravett E, Gilmour K, Lal A, Kunaseelan S, Popova B, Lopes A, Ngai Y, Hackshaw A, Kokalaki E, Carulla MB, Mullanfiroze K, Lazareva A, Pavasovic V, Rao A, Bartram J, Vora A, Chiesa R, Silva J, Rao K, Bonney PMID 37647647
• Kokalaki E, Ma B, Ferrari M, Grothier T, Hazelton W, Manzoor S, Costu E, Taylor J, Bulek A, Srivastava S, Gannon I, Jha R, Gealy R, Stanczuk L, Rizou T, Robson M, El-Kholy M, Baldan V, Righi M, Sillibourne J, Thomas S, Onuoha S, Cordoba S, Pule M. Dual targeting of CD19 and CD22 against B-ALL using a novel high-sensitivity aCD22 CAR. Mol Ther. 2023 Jul 5;31(7):2089-2104. doi: 10.1016/j.ymthe.2023. PMID 36945773
• Ghorashian S, Kramer AM, Onuoha S, Wright G, Bartram J, Richardson R, Albon SJ, Casanovas-Company J, Castro F, Popova B, Villanueva K, Yeung J, Vetharoy W, Guvenel A, Wawrzyniecka PA, Mekkaoui L, Cheung GW, Pinner D, Chu J, Lucchini G, Silva J, Ciocarlie O, Lazareva A, Inglott S, Gilmour KC, Ahsan G, Ferrari M, Manzoor S, Champion K, Brooks T, Lopes A, Hackshaw A, Farzaneh F, Chiesa R, Rao K, Bonn PMID 31477906

Identifiers

NCT: NCT02443831 · UCL 14/0529

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗