Clinical trial NCT03298828: CD19 CAR and PD-1 Knockout Engineered T Cells for CD19 Positive Malignant B-cell Derived Leukemia and Lymphoma
Official title: CD19 Chimeric Antigen Receptor (CAR) and PD-1 Knockout Engineered T Cells for CD19 Positive Malignant B-cell Derived Leukemia and Lymphoma
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Acute Lymphoblastic Leukemia
Burkitt Lymphoma
Lead sponsor: Third Military Medical University
Sponsor class: OTHER
First posted: 2017-10-02
Enrollment: 30
Sex: ALL
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety, efficacy and blood kinetics of autologous T cells genetically modified to express CD19 Chimeric Antigen Receptor and PD-1 knockout engineered T cells in patients with relapsed or refractory B-Cell Non-Hodgkin Lymphoma and 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 Chimeric Antigen Receptor (CAR) and PD-1 knock out engineered T-cells (CD19 CAR and PD-1 knock out engineered T-cells) in children and adults (age \<70 years) with high risk, relapsed CD19+ 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 CAR T-cells. Patients will receive the CD19 CAR and PD-1 knock out engineered T-cells following lymphodepleting chemotherapy. The study will evaluate the safety, efficacy and duration of response of the CD19 CAR and PD-1 knock out engineered T-cells in children with high risk relapsed CD19+ malignancies.

Eligibility criteria: Inclusion Criteria:

* 1.Children and adults (age 70 years or younger) with high risk/relapsed CD19+ haematological malignancy:

  1. Resistant disease (\>25% blasts) at end of UKALL 2011 or equivalent induction
  2. ALL with persistent high level MRD at 2nd time point of frontline national protocol (currently \> 5 x 10-3 at week 14 UKALL2011 or equivalent)
  3. 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 Interfant 06)
  4. Intermediate risk infant ALL with MRD \> 10-3 at end of Interfant06 induction
  5. Very early (\< 18 months from diagnosis) bone marrow or extramedullary relapse of acute lymphoblastic leukaemia (ALL)
  6. Early (within 6 months of finishing therapy) bone marrow, or combined extramedullary relapse of ALL with bone marrow minimal residual disease (MRD) \> 10-3 at end of re-induction
  7. Any on therapy relapse of ALL in patients age 16-70
  8. Any relapse of infant ALL
  9. ALL post ≥ 2nd relapse
  10. Any refractory relapse of ALL
  11. ALL with MRD \>10-4 prior to planned stem cell transplant
  12. Any relapse of ALL eligible for stem cell transplant but no available HLA matched donor or other contraindication to transplant
  13. Any relapse of ALL after stem cell transplant
  14. Any relapse of Burkitt's or other CD19+ lymphoma
* 2.Agreement to have a pregnancy test, use adequate contraception (if applicable)
* 3.Written informed consent

Exclusion Criteria:

* Exclusion Criteria for registration:

  1. CD19 negative disease
  2. Active hepatitis B, C or HIV infection
  3. Oxygen saturation ≤ 90% on air
  4. Bilirubin \> 3 x upper limit of normal
  5. Creatinine \> 3 x upper limit of normal
  6. Women who are pregnant or lactating
  7. Stem Cell Transplant patients only: active acute graft-versus-host disease (GVHD) overall Grade ≥ II (Seattle criteria) or moderate/severe chronic GVHD (NIH consensus criteria) requiring systemic steroids
  8. Inability to tolerate leucapheresis
  9. Karnofsky (age ≥ 10 years) or Lansky (age \< 10) score ≤ 50%
* Exclusion criteria for CD19CAR T-cell infusion:

  1. Severe intercurrent infection at the time of scheduled CD19 CAR and PD-1 Knockout Engineered T Cells infusion
  2. Requirement for supplementary oxygen or active pulmonary infiltrates at the time of scheduled CD19 CAR and PD-1 Knockout Engineered T Cells infusion
  3. Allogeneic transplant recipients with active acute GVHD overall grade \>2 or moderate/severe chronic GVHD requiring systemic steroids at the time of scheduled CD19 CAR and PD-1 Knockout Engineered T Cells infusion

Primary outcomes:
measure: Molecular remission
timeFrame: 1 month
Secondary outcomes:
measure: Long term molecular remission
timeFrame: 2 years
measure: Frequency of circulating CD19 CAR and PD-1 Knockout Engineered T-cells
timeFrame: 2 years
measure: Incidence of hypogammaglobulinaemia
timeFrame: 2 years
measure: Relapse rate
timeFrame: 10 years
measure: Overall Survival
timeFrame: 10 years
Other outcomes:
Locations:
Study officials:
References: