search
Back to results

Exploratory Study of CD19-targeted Chimeric Antigen Receptor T Cells(BZ019) for Relapsed and Refractory B-cell Lymphoma

Primary Purpose

Diffuse Large B Cell Lymphoma, High-grade B-cell Lymphoma, Transformed Lymphoma

Status
Unknown status
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
BZ019
Sponsored by
Institute of Hematology & Blood Diseases Hospital, China
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diffuse Large B Cell Lymphoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Written informed consent must be obtained prior to any screening procedures
  2. Age ≥ 18 years subjects with Relapsed or refractory large B-cell lymphoma, including: DLBCL,NOS, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, transformed B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBCL).

    • No response for the last chemotherapy:

      • Progressive disease after the last chemotherapy or
      • Stable disease after the last chemotherapy, and the maintenance time for stable disease was no longer than 6 month after last dose.
    • Either having failed autologous Hematopoietic stem cell transplantation (ASCT), or being ineligible for or not consenting to ASCT

      • Refractory disease after ASCT or relapsed disease within 12 months after last ASCT (histologically confirmed) or
      • No response or relapsed disease for the last therapy after ASCT.
  3. Subjects must be accepted adequate treatment, including at least:

    • Treated by CD20 monoclonal antibody (Rituximab) except for CD20 negative.
    • Chemotherapy including anthracycline
  4. Measurable disease at time of enrollment according to the revised international working group response criteria for malignant lymphoma.
  5. Life expectancy ≥12 weeks
  6. Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1 at screening.
  7. Adequate organ function:

    • Renal function defined as:

      • A serum creatinine of ≤1.5 x Upper Limit of Normal(ULN) or
      • Estimated Glomerular Filtration Rate (eGFR) ≥ 60 mL/min/1.73 m2
    • Liver function defined as:

      • Alanine Aminotransferase (ALT) ≤ 5 times the ULN for age
      • Bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert-Meulengracht syndrome; patients with Gilbert-Meulengracht syndrome may be included if their total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN
    • Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygenation > 91% on room air
  8. Hemodynamically stable and Left Ventricle Ejection Fraction (LVEF) ≥ 45% confirmed by echocardiogram or Multigated Radionuclide Angiography (MUGA)
  9. Adequate bone marrow reserve without transfusions defined as:

    • Absolute neutrophil count (ANC) > 1000/μL
    • Absolute lymphocyte count (ALC) ≥ 300/μL
    • Platelets ≥ 50000/μL
    • Hemoglobin > 8.0 g/dl
  10. Must have an apheresis product of non-mobilized cells accepted for manufacturing.
  11. The following medications are excluded:

    • Steroids: Therapeutic doses of steroids must be stopped > 72 hours prior to BZ019 infusion. However, the following physiological replacement doses of steroids are allowed: < 6 - 12 mg/m2/day hydrocortisone or equivalent
    • Immunosuppression: Any immunosuppressive medication must be stopped ≥ 4 weeks prior to enrollment
    • Antiproliferative therapies other than lymphodepleting chemotherapy within two weeks of infusion
    • Antibody use including anti-CD20 therapy within 4 weeks prior to infusion or 5 half-lives of the respected antibody, whichever is longer
    • CNS disease prophylaxis must be stopped > 1 week prior to BZ019 infusion (e.g. intrathecal methotrexate)
  12. Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants must agree to use highly effective methods of contraception for at least 12 months following BZ019 infusion and until CAR T cells are no longer present by PCR on two consecutive tests

Exclusion Criteria:

  1. Prior treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy
  2. Treatment with any prior gene therapy product, include CAR-T cell therapy.
  3. Active Central Nervous System (CNS) involvement by malignancy or secondary CNS involvement
  4. History or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or self-immune disease with CNS involvement.
  5. Prior allogeneic HSCT
  6. Eligible for and consenting to ASCT
  7. Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of infusion
  8. Investigational medicinal product within the last 30 days prior to screening
  9. Prior radiation therapy within 2 weeks of infusion
  10. Active replication of or prior infection with hepatitis B or active hepatitis C( HCV RNA positive )
  11. HIV positive patients
  12. Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to infusion)
  13. Unstable angina and/or myocardial infarction within 6 months prior to screening
  14. Previous or concurrent malignancy with the following exceptions:

    • Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry)
    • In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to the study
    • A primary malignancy which has been completely resected and in complete remission for ≥ 5 years
  15. Pregnant or nursing (lactating) women
  16. Cardiac arrhythmia not controlled with medical management
  17. Patients on oral anticoagulation therapy within 1 week prior to BZ019 infusion.
  18. Prior treatment with any adoptive T cell therapy
  19. Patients with active neurological auto immune or inflammatory disorders(e.g. Guillain Barre Syndrome, Amyotrophic Lateral Sclerosis)
  20. Other protocol-related inclusion/exclusion may apply.

Sites / Locations

  • Institute of Hematology & Blood Diseases Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

BZ019 treatment

Arm Description

Subjects will receive lymphodepleting chemotherapy of fludarabine and cyclophosphamide (flu/cy) followed by single-dose of BZ019 infusion. A 3×3 dose escalation design of BZ019 will be adopted.

Outcomes

Primary Outcome Measures

Number of adverse events
Number of BZ019 therapy associated adverse events, such as cytokine release syndrome(CRS), chimeric antigen receptor (CAR)-T cell related encephalopathy syndrome(CRES) or other adverse events.

Secondary Outcome Measures

proliferation of BZ019 in vivo
measured by PCR
Overall response rate
CR+PR

Full Information

First Posted
January 7, 2019
Last Updated
March 15, 2020
Sponsor
Institute of Hematology & Blood Diseases Hospital, China
Collaborators
Shanghai Cell Therapy Engineering Technology Research Center Group Co., Ltd.
search

1. Study Identification

Unique Protocol Identification Number
NCT04067414
Brief Title
Exploratory Study of CD19-targeted Chimeric Antigen Receptor T Cells(BZ019) for Relapsed and Refractory B-cell Lymphoma
Official Title
A Single Cohort, Open-label, Multicenter, Dose-escalation Study of Safety and Efficacy of BZ019 for Adult CD19 Positive Relapsed and Refractory B-cell Non-Hodgkin Lymphoma
Study Type
Interventional

2. Study Status

Record Verification Date
March 2020
Overall Recruitment Status
Unknown status
Study Start Date
June 14, 2018 (Actual)
Primary Completion Date
July 31, 2020 (Anticipated)
Study Completion Date
December 31, 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Institute of Hematology & Blood Diseases Hospital, China
Collaborators
Shanghai Cell Therapy Engineering Technology Research Center Group Co., Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is an open-label, multicenter, dose-escalation phase 1 study to determine the safety and efficacy of BZ019 in relapsed or refractory CD19+ B-cell Lymphoma.
Detailed Description
This is an open-label, multicenter, phase 1 study to determine the safety and antitumor activity of BZ019 in adult patients with R/R large B cell lymphoma (DLBCL),including: DLBCL, not otherwise specified (NOS), transformed DLBCL, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements and primary mediastinal B-cell lymphoma (PMBCL).The safety and efficacy of a single dose of different target doses of BZ019 will be evaluated in the dose-escalation phase and dose-expansion phase. Upon enrollment, subjects will undergo leukapheresis to enable BZ019 product generation. A baseline tumor biopsy (in subjects with accessible disease) and bone marrow aspirate and biopsy will be obtained. Upon successful BZ019 product generation, subjects will enter the treatment phase and receive BZ019 infusion. A completed treatment program will include lymphodepleting chemotherapy with fludarabine and cyclophosphamide (flu/cy) followed by single-dose of BZ019 infusion. BZ019 will be administered 2 to 14 days after the completion of lymphodepleting chemotherapy. After the infusion of BZ019, subjects will be in the follow-up period upon 12 months for evaluation the safety and efficacy of BZ019. Subjects will be followed for long-term safety, overall survival even after disease progression.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diffuse Large B Cell Lymphoma, High-grade B-cell Lymphoma, Transformed Lymphoma, Primary Mediastinal Large B Cell Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Model Description
A treatment program will include lymphodepleting chemotherapy with fludarabine and cyclophosphamide (flu/cy) followed by single-dose of BZ019 administered intravenously (IV). A 3×3 dose escalation design of BZ019 will be adopted.
Masking
None (Open Label)
Enrollment
12 (Actual)

8. Arms, Groups, and Interventions

Arm Title
BZ019 treatment
Arm Type
Experimental
Arm Description
Subjects will receive lymphodepleting chemotherapy of fludarabine and cyclophosphamide (flu/cy) followed by single-dose of BZ019 infusion. A 3×3 dose escalation design of BZ019 will be adopted.
Intervention Type
Biological
Intervention Name(s)
BZ019
Intervention Description
Subjects will be enrolled in three dose-groups: Dose 1: 1×10^6/kg CAR+ cells; Dose 2: 3×10^6/kg CAR+ cells; Dose 3: 6×10^6/kg CAR+ cells.
Primary Outcome Measure Information:
Title
Number of adverse events
Description
Number of BZ019 therapy associated adverse events, such as cytokine release syndrome(CRS), chimeric antigen receptor (CAR)-T cell related encephalopathy syndrome(CRES) or other adverse events.
Time Frame
up to 1 year after BZ019 infusion.
Secondary Outcome Measure Information:
Title
proliferation of BZ019 in vivo
Description
measured by PCR
Time Frame
up to 1 year after BZ019 infusion.
Title
Overall response rate
Description
CR+PR
Time Frame
up to 1 year after BZ019 infusion.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Written informed consent must be obtained prior to any screening procedures Age ≥ 18 years subjects with Relapsed or refractory large B-cell lymphoma, including: DLBCL,NOS, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, transformed B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBCL). No response for the last chemotherapy: Progressive disease after the last chemotherapy or Stable disease after the last chemotherapy, and the maintenance time for stable disease was no longer than 6 month after last dose. Either having failed autologous Hematopoietic stem cell transplantation (ASCT), or being ineligible for or not consenting to ASCT Refractory disease after ASCT or relapsed disease within 12 months after last ASCT (histologically confirmed) or No response or relapsed disease for the last therapy after ASCT. Subjects must be accepted adequate treatment, including at least: Treated by CD20 monoclonal antibody (Rituximab) except for CD20 negative. Chemotherapy including anthracycline Measurable disease at time of enrollment according to the revised international working group response criteria for malignant lymphoma. Life expectancy ≥12 weeks Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1 at screening. Adequate organ function: Renal function defined as: A serum creatinine of ≤1.5 x Upper Limit of Normal(ULN) or Estimated Glomerular Filtration Rate (eGFR) ≥ 60 mL/min/1.73 m2 Liver function defined as: Alanine Aminotransferase (ALT) ≤ 5 times the ULN for age Bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert-Meulengracht syndrome; patients with Gilbert-Meulengracht syndrome may be included if their total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygenation > 91% on room air Hemodynamically stable and Left Ventricle Ejection Fraction (LVEF) ≥ 45% confirmed by echocardiogram or Multigated Radionuclide Angiography (MUGA) Adequate bone marrow reserve without transfusions defined as: Absolute neutrophil count (ANC) > 1000/μL Absolute lymphocyte count (ALC) ≥ 300/μL Platelets ≥ 50000/μL Hemoglobin > 8.0 g/dl Must have an apheresis product of non-mobilized cells accepted for manufacturing. The following medications are excluded: Steroids: Therapeutic doses of steroids must be stopped > 72 hours prior to BZ019 infusion. However, the following physiological replacement doses of steroids are allowed: < 6 - 12 mg/m2/day hydrocortisone or equivalent Immunosuppression: Any immunosuppressive medication must be stopped ≥ 4 weeks prior to enrollment Antiproliferative therapies other than lymphodepleting chemotherapy within two weeks of infusion Antibody use including anti-CD20 therapy within 4 weeks prior to infusion or 5 half-lives of the respected antibody, whichever is longer CNS disease prophylaxis must be stopped > 1 week prior to BZ019 infusion (e.g. intrathecal methotrexate) Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants must agree to use highly effective methods of contraception for at least 12 months following BZ019 infusion and until CAR T cells are no longer present by PCR on two consecutive tests Exclusion Criteria: Prior treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy Treatment with any prior gene therapy product, include CAR-T cell therapy. Active Central Nervous System (CNS) involvement by malignancy or secondary CNS involvement History or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or self-immune disease with CNS involvement. Prior allogeneic HSCT Eligible for and consenting to ASCT Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of infusion Investigational medicinal product within the last 30 days prior to screening Prior radiation therapy within 2 weeks of infusion Active replication of or prior infection with hepatitis B or active hepatitis C( HCV RNA positive ) HIV positive patients Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to infusion) Unstable angina and/or myocardial infarction within 6 months prior to screening Previous or concurrent malignancy with the following exceptions: Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry) In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to the study A primary malignancy which has been completely resected and in complete remission for ≥ 5 years Pregnant or nursing (lactating) women Cardiac arrhythmia not controlled with medical management Patients on oral anticoagulation therapy within 1 week prior to BZ019 infusion. Prior treatment with any adoptive T cell therapy Patients with active neurological auto immune or inflammatory disorders(e.g. Guillain Barre Syndrome, Amyotrophic Lateral Sclerosis) Other protocol-related inclusion/exclusion may apply.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lugui Qiu, MD
Organizational Affiliation
Institute of Hematology & Blood Diseases Hospital, China
Official's Role
Principal Investigator
Facility Information:
Facility Name
Institute of Hematology & Blood Diseases Hospital
City
Tianjin
ZIP/Postal Code
300020
Country
China

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Exploratory Study of CD19-targeted Chimeric Antigen Receptor T Cells(BZ019) for Relapsed and Refractory B-cell Lymphoma

We'll reach out to this number within 24 hrs