Back to resultsCD19 CAR and PD-1 Knockout Engineered T Cells for CD19 Positive Malignant B-cell Derived Leukemia and Lymphoma
Primary Purpose
Acute Lymphoblastic Leukemia, Burkitt Lymphoma
Status
Unknown status
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
CD19 CAR and PD-1 knock out engineered T-cells
CD19 CAR T-cells
Sponsored by
About this trial
This is an interventional treatment trial for Acute Lymphoblastic Leukemia
Eligibility Criteria
Inclusion Criteria:
1.Children and adults (age 70 years or younger) with high risk/relapsed CD19+ haematological malignancy:
- Resistant disease (>25% blasts) at end of UKALL 2011 or equivalent induction
- 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)
- 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)
- Intermediate risk infant ALL with MRD > 10-3 at end of Interfant06 induction
- Very early (< 18 months from diagnosis) bone marrow or extramedullary relapse of acute lymphoblastic leukaemia (ALL)
- 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
- Any on therapy relapse of ALL in patients age 16-70
- Any relapse of infant ALL
- ALL post ≥ 2nd relapse
- Any refractory relapse of ALL
- 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
- 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:
- CD19 negative disease
- 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 lactating
- 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
- Inability to tolerate leucapheresis
- Karnofsky (age ≥ 10 years) or Lansky (age < 10) score ≤ 50%
Exclusion criteria for CD19CAR T-cell infusion:
- Severe intercurrent infection at the time of scheduled CD19 CAR and PD-1 Knockout Engineered T Cells infusion
- Requirement for supplementary oxygen or active pulmonary infiltrates at the time of scheduled CD19 CAR and PD-1 Knockout Engineered T Cells infusion
- 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
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
CD19 CAR
CD19 CAR and PD-1 knock out
Arm Description
Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19 CAR T-cells. Patients will receive lymphodepletion with fludarabine and cyclophosphamide prior to infusion of the CD19 CAR T-cells.
Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19 CAR and PD-1 knock out engineered T-cells. Patients will receive lymphodepletion with fludarabine and cyclophosphamide prior to infusion of the CD19 CAR and PD-1 knock out engineered T-cells.
Outcomes
Primary Outcome Measures
Molecular remission
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 1 month post CD19 CAR and PD-1 Knockout Engineered T-cell infusion will be determined.
Secondary Outcome Measures
Long term molecular remission
Number of patients in molecular remission without further therapy at 2 years
Frequency of circulating CD19 CAR and PD-1 Knockout Engineered T-cells
Persistence and frequency of circulating CD19 CAR and PD-1 Knockout Engineered T-cells in the peripheral blood by flow cytometry and qPCR analyses.
Incidence of hypogammaglobulinaemia
Incidence and duration of hypogammaglobulinaemia.
Relapse rate
Relapse rate monitored during interventional phase and long term follow up for a total of 10 years post cell infusion. Number of patients who relapsed can be summarized as a percentage (for all patients registered to the trial, and also only for those who received the cell infusion).
Overall Survival
Overall survival is monitored during interventional phase and long term follow up for 10 years post-CD19 CAR and PD-1 Knockout Engineered T-cell infusion. Number of patients alive can be summarized as a percentage (for all patients registered to the trial, and also only for those who received the cell infusion).
Full Information
NCT ID
NCT03298828
First Posted
July 24, 2017
Last Updated
September 26, 2017
Sponsor
Third Military Medical University
1. Study Identification
Unique Protocol Identification Number
NCT03298828
Brief Title
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
2. Study Status
Record Verification Date
September 2017
Overall Recruitment Status
Unknown status
Study Start Date
November 2017 (Anticipated)
Primary Completion Date
October 2020 (Anticipated)
Study Completion Date
October 2022 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Third Military Medical University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Lymphoblastic Leukemia, Burkitt Lymphoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
30 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
CD19 CAR
Arm Type
Experimental
Arm Description
Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19 CAR T-cells. Patients will receive lymphodepletion with fludarabine and cyclophosphamide prior to infusion of the CD19 CAR T-cells.
Arm Title
CD19 CAR and PD-1 knock out
Arm Type
Experimental
Arm Description
Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19 CAR and PD-1 knock out engineered T-cells. Patients will receive lymphodepletion with fludarabine and cyclophosphamide prior to infusion of the CD19 CAR and PD-1 knock out engineered T-cells.
Intervention Type
Biological
Intervention Name(s)
CD19 CAR and PD-1 knock out engineered T-cells
Intervention Description
A single dose of 1 x 10^6/kg CD19 CAR transduced and PD-1 knock out engineered T-cells will be given as an intravenous injection through a Hickman line or PICC line(peripherally inserted central catheter) on day 0.
Intervention Type
Biological
Intervention Name(s)
CD19 CAR T-cells
Intervention Description
A single dose of 1 x 10^6/kg CD19 CAR transduced T-cells will be given as an intravenous injection through a Hickman line or PICC line(peripherally inserted central catheter) on day 0.
Primary Outcome Measure Information:
Title
Molecular remission
Description
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 1 month post CD19 CAR and PD-1 Knockout Engineered T-cell infusion will be determined.
Time Frame
1 month
Secondary Outcome Measure Information:
Title
Long term molecular remission
Description
Number of patients in molecular remission without further therapy at 2 years
Time Frame
2 years
Title
Frequency of circulating CD19 CAR and PD-1 Knockout Engineered T-cells
Description
Persistence and frequency of circulating CD19 CAR and PD-1 Knockout Engineered T-cells in the peripheral blood by flow cytometry and qPCR analyses.
Time Frame
2 years
Title
Incidence of hypogammaglobulinaemia
Description
Incidence and duration of hypogammaglobulinaemia.
Time Frame
2 years
Title
Relapse rate
Description
Relapse rate monitored during interventional phase and long term follow up for a total of 10 years post cell infusion. Number of patients who relapsed can be summarized as a percentage (for all patients registered to the trial, and also only for those who received the cell infusion).
Time Frame
10 years
Title
Overall Survival
Description
Overall survival is monitored during interventional phase and long term follow up for 10 years post-CD19 CAR and PD-1 Knockout Engineered T-cell infusion. Number of patients alive can be summarized as a percentage (for all patients registered to the trial, and also only for those who received the cell infusion).
Time Frame
10 years
10. Eligibility
Sex
All
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
1.Children and adults (age 70 years or younger) with high risk/relapsed CD19+ haematological malignancy:
Resistant disease (>25% blasts) at end of UKALL 2011 or equivalent induction
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)
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)
Intermediate risk infant ALL with MRD > 10-3 at end of Interfant06 induction
Very early (< 18 months from diagnosis) bone marrow or extramedullary relapse of acute lymphoblastic leukaemia (ALL)
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
Any on therapy relapse of ALL in patients age 16-70
Any relapse of infant ALL
ALL post ≥ 2nd relapse
Any refractory relapse of ALL
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
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:
CD19 negative disease
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 lactating
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
Inability to tolerate leucapheresis
Karnofsky (age ≥ 10 years) or Lansky (age < 10) score ≤ 50%
Exclusion criteria for CD19CAR T-cell infusion:
Severe intercurrent infection at the time of scheduled CD19 CAR and PD-1 Knockout Engineered T Cells infusion
Requirement for supplementary oxygen or active pulmonary infiltrates at the time of scheduled CD19 CAR and PD-1 Knockout Engineered T Cells infusion
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Xiaoyun Shang, Dr.
Phone
+8618580607020
Email
shangxiaoyun@gmail.com
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Learn more about this trial
CD19 CAR and PD-1 Knockout Engineered T Cells for CD19 Positive Malignant B-cell Derived Leukemia and Lymphoma
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