CD19 CAR and PD-1 Knockout Engineered T Cells for CD19 Positive Malignant B-cell Derived Leukemia and Lymphoma

CD19 Chimeric Antigen Receptor (CAR) and PD-1 Knockout Engineered T Cells for CD19 Positive Malignant B-cell Derived Leukemia and Lymphoma

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.

Study Overview

• Status: Unknown
• Conditions: Burkitt Lymphoma; Acute Lymphoblastic Leukemia
• Intervention / Treatment: Biological: CD19 CAR T-cells; Biological: CD19 CAR and PD-1 knock out engineered T-cells

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.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Xiaoyun Shang, Dr.; Phone Number: +8618580607020; Email: shangxiaoyun@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CD19 CAR; 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.	Biological: CD19 CAR T-cells; 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.
Experimental: CD19 CAR and PD-1 knock out; 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.	Biological: CD19 CAR and PD-1 knock out engineered T-cells; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Long term molecular remission	Number of patients in molecular remission without further therapy at 2 years	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.	2 years
Incidence of hypogammaglobulinaemia	Incidence and duration of hypogammaglobulinaemia.	2 years
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).	10 years
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).	10 years

Collaborators and Investigators

• Sponsor: Third Military Medical University

Study record dates

Study Major Dates

• Study Start (Anticipated): November 1, 2017
• Primary Completion (Anticipated): October 1, 2020
• Study Completion (Anticipated): October 1, 2022

Study Registration Dates

• First Submitted: July 24, 2017
• First Submitted That Met QC Criteria: September 26, 2017
• First Posted (Actual): October 2, 2017

Study Record Updates

• Last Update Posted (Actual): October 2, 2017
• Last Update Submitted That Met QC Criteria: September 26, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Virus Diseases; Infections; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; DNA Virus Infections; Tumor Virus Infections; Leukemia, Lymphoid; Epstein-Barr Virus Infections; Herpesviridae Infections; Lymphoma, B-Cell; Lymphoma; Leukemia; Burkitt Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Other Study ID Numbers: TMMU-CAR-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No