Clinical trial NCT02443831: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Acute Lymphoblastic Leukemia
Keywords: high risk relapsed CD19+ and CD22+ acute lymphoblastic leukaemia
Lead sponsor: University College, London
Sponsor class: OTHER
First posted: 2015-05-14
Enrollment: 50
Sex: ALL
Maximum age (years): 24
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of dose limiting toxicity (DLT) following CD19+CD22 CAR T-cell infusion
timeFrame: 28 days
measure: Molecular remission
timeFrame: 28 days
Secondary outcomes:
measure: Feasibility of Generation of CD19+CD22 CAR T-cells
timeFrame: Day 28
measure: Molecular Remission
timeFrame: 3 months
measure: Long-Term Molecular Remission
timeFrame: 2 years
measure: Duration of Response
timeFrame: 15 years
measure: Safety and Tolerability of the CAR T-cells
timeFrame: 15 years
measure: Incidence of B Aplasia
timeFrame: 2 years
measure: Incidence of Hypogammaglobulinaemia
timeFrame: 2 years
measure: Frequency of Circulating CD19+CD22 CAR T-cells
timeFrame: 2 years
measure: Relapse rate
timeFrame: 2 years
measure: Overall Survival (OS)
timeFrame: 2 years
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
city: London
country: United Kingdom
facility: University College Hospital
city: Manchester
country: United Kingdom
facility: Manchester Royal Children's Hospital
Study officials:
affiliation: UCL Institute of Child Health
name: Persis Amrolia
role: STUDY_CHAIR
References:
citation: 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, Bonney D, Samarasinghe S, Goulden N, Vora A, Veys P, Hough R, Wynn R, Pule MA, Amrolia PJ. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat Med. 2019 Sep;25(9):1408-1414. doi: 10.1038/s41591-019-0549-5. Epub 2019 Sep 2.