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Study of Safety and Efficacy of BZ019 in (R/R) Large B-cell Lymphoma

Primary Purpose

Large B-cell Lymphoma

Status
Unknown status
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
BZ019
Sponsored by
Shanghai Cell Therapy Group Co.,Ltd
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Large B-cell Lymphoma

Eligibility Criteria

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

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, only DLBCL non-specific type, primary mediastinal large B-cell lymphoma, follicular lymphoma transformed large B-cell lymphoma, advanced B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement, advanced B-cell lymphoma non-specific type. The definition of refractory is as follows:

    • no response to the last treatment, including:The best response to the latest treatment is disease progression (PD), or the best response to the latest treatment plan is disease stability (SD) and the maintenance time is not more than 6 months after the last administration;
    • or not suitable for autologous hematopoietic stem cell transplantation (ASCT), or ASCT refractory, including: disease progression after ASCT or recurrence within ≤ 12 months (recurrence must be confirmed by biopsy), or if receiving remedial treatment after ASCT, the subject must have no reaction or recurrence after the last treatment.
  • Subjects must be accepted adequate treatment before and have received at least 2 lines of treatment or relapse or progress after autologous hematopoietic stem cell transplantation, and the treatment history at least include:

    • Treatment by CD20 monoclonal antibody (Rituximab) except for CD20 negative;
    • a chemotherapy regimen containing anthracyclines.
  • According to the preliminary evaluation, staging and response evaluation recommendations for Hodgkin and non Hodgkin's lymphoma (2014 Edition), at least one measurable lesion was found in the screening period.
  • Life expectancy ≥12 weeks.
  • Baseline Eastern Cooperative Oncology Group (ECOG) score is 0 or 1 .
  • Adequate organ function:

    • Renal function defined as:A serum creatinine of ≤1.5 x ULN or Estimated Glomerular Filtration Rate (eGFR) ≥ 60 mL/min/1.73 m^2;
    • Liver function defined as:Alanine Aminotransferase (ALT) ≤ 5 x ULN;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) ≥ 50%, confirmed by echocardiogram or Multigated Radionuclide Angiography (MUGA).
  • No blood transfusion within 1 week before signing the informed consent, sufficient bone marrow reserve is available, which is defined as:

    • Absolute neutrophil count (ANC) > 1000/μl;
    • Absolute lymphocyte count (ALC) ≥ 500/μl;
    • Platelets ≥ 50000/μl;
    • Hemoglobin > 8.0 g/dl, for patients with bone marrow invasion, hemoglobin > 6.0 g/dl can be considered into the group.
  • Must have an apheresis product of non-mobilized cells accepted for manufacturing.
  • If the patient uses the following drugs, the following conditions should be met:

    • glucocorticoids: The treatment dose of glucocorticoids must be stopped 72 hours before BZ019 infusion. However, glucocorticoids of physiological alternative dose are allowed: prednisone or its equivalent ≤ 15 mg / day;
    • 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 age and all male subjects must agree to use effective contraceptive methods until BZ019 are no longer present in the body (detected by PCR).

Exclusion Criteria:

  • Patients who have previously received any anti-CD45, anti-CD19 or anti-CD3 therapy;
  • Patients who have previously received any adoptive T cell therapy or gene therapy products, including CAR-T 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.
  • 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 6 weeks of infusion.
  • Patients with positive hepatitis B (HBsAg and / or HBcAb positive, except for those with positive surface antibody alone) or hepatitis C serological markers;
  • HIV positive or Treponema pallidum positive patients.
  • Patients with uncontrollable active or life-threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours before infusion);
  • Patients with unstable angina and / or myocardial infarction within 6 months before screening, or patients with serious or uncontrollable other diseases (such as unstable or uncompensated respiratory, heart, liver or kidney diseases) during 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.
  • Patients with uncontrolled arrhythmia.
  • Patients on oral anticoagulation therapy within 1 week prior to BZ019 infusion.
  • Patients with active neurological auto immune or inflammatory disorders(e.g. Guillain Barre Syndrome, Amyptrophic Lateral Sclerosis)
  • Other protocol-related inclusion/exclusion may apply.

Sites / Locations

  • Hematology Hospital, Chinese Academy of Medical SciencesRecruiting
  • Tianjin medical university cancer institute and hospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

BZ019

Arm Description

The subjects are enrolled into 2 dose-escalation cohorts, include 3x10^6/kg、6x10^6/kg, and dose-expansion cohorts, maybe 8x10^6/kg、10x10^6/kg.

Outcomes

Primary Outcome Measures

Dose-limiting toxicity (DLT)
Safety
Maximum tolerated dose (MTD)
Tolerability

Secondary Outcome Measures

Pharmacokinetics(the copies of cells in vivo)
Pharmacokinetics is defined as the number of copies of BZ019 DNA in peripheral blood at each visit after infusion until the test results are negative or below the detection limit. It aims to calculate the Peak Plasma Concentration (Cmax)
Pharmacokinetics(the duration of survival of cells in vivo)
Duration of BZ019 persistence is the period from the day of infusion to the first negative test result. It aims to calculate the area under the plasma concentration versus time curve (AUC)
Pharmacodynamics
Pharmacodynamics is defined as the level of Cytokine, at least include IL-2, IL-4, IL-6, IL-10, IL-15, IFN-γ, TNF-α. The peak value of cytokines and their return to baseline were evaluated
Antitumor efficacy-Objective response rate (ORR)
The number of cases in which tumor size is reduced to PR or CR / the total number of evaluable cases (%)
Antitumor efficacy-Overall survival (OS)
The period from the first infusion to any cause of death
Antitumor efficacy-Progression-free survival (PFS)
The period from the day when the subject receives the infusion of cells to the first recorded tumor progression (whether treated or not) or death of any cause, which occurs first.
Antitumor efficacy-event -free survival (EFS)
Event free survival rate refers to the time from enrollment to occurrence of any event, including death, disease progression, change of chemotherapy program, change to chemotherapy, additional treatment, occurrence of lethal or intolerable side effects and other events.
Antitumor efficacy- Tumor progression time (TTP)
Tumor progression time refers to the time from the beginning of the infusion of cells to tumor progression

Full Information

First Posted
January 30, 2020
Last Updated
January 30, 2020
Sponsor
Shanghai Cell Therapy Group Co.,Ltd
Collaborators
Institute of Hematology & Blood Diseases Hospital, China, Tianjin Medical University Cancer Institute and Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT04250324
Brief Title
Study of Safety and Efficacy of BZ019 in (R/R) Large B-cell Lymphoma
Official Title
A Phase I Clinical Study of CD19-targeted Chimeric Antigen Receptor (CAR) T Cells Injection, for Relapsed and Refractory (R/R) Large B-cell Lymphoma
Study Type
Interventional

2. Study Status

Record Verification Date
January 2020
Overall Recruitment Status
Unknown status
Study Start Date
November 19, 2019 (Actual)
Primary Completion Date
August 2022 (Anticipated)
Study Completion Date
December 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Shanghai Cell Therapy Group Co.,Ltd
Collaborators
Institute of Hematology & Blood Diseases Hospital, China, Tianjin Medical University Cancer Institute and Hospital

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 subjects.
Detailed Description
This is an open-label, multicenter, phase 1 study to determine the safety, PK, and antitumor activity of BZ019 in adult subjects with R/R large CD19+B cell lymphoma. 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. Primary objectives: - To evaluate the safety and tolerance of single infusion of BZ019 in adult patients with relapsed or refractory large B-cell lymphoma, and to determine the maximum tolerable dose (MTD) and phase II recommended dose. Secondary objectives: To evaluate the pharmacokinetics and survival of BZ019 in the peripheral blood of adult patients with relapsed or refractory large B-cell lymphoma; To evaluate the Pharmacodynamic characteristics of BZ019 in adult patients with relapsed or refractory large B-cell lymphoma; Objective response rate (ORR), Overall survival, progression free survival, event free survival, and tumor progression time were used to evaluate the antitumor efficacy of BZ019 in the treatment of relapsed or refractory large B-cell lymphoma.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Large B-cell Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
21 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
BZ019
Arm Type
Experimental
Arm Description
The subjects are enrolled into 2 dose-escalation cohorts, include 3x10^6/kg、6x10^6/kg, and dose-expansion cohorts, maybe 8x10^6/kg、10x10^6/kg.
Intervention Type
Biological
Intervention Name(s)
BZ019
Intervention Description
A treatment program will include lymphodepleting chemotherapy with fludarabine and cyclophosphamide (flu/cy) followed by single-dose of BZ019 administered intravenously (IV).
Primary Outcome Measure Information:
Title
Dose-limiting toxicity (DLT)
Description
Safety
Time Frame
After 28 days of single infusion
Title
Maximum tolerated dose (MTD)
Description
Tolerability
Time Frame
After 28 days of single infusion
Secondary Outcome Measure Information:
Title
Pharmacokinetics(the copies of cells in vivo)
Description
Pharmacokinetics is defined as the number of copies of BZ019 DNA in peripheral blood at each visit after infusion until the test results are negative or below the detection limit. It aims to calculate the Peak Plasma Concentration (Cmax)
Time Frame
Month 24
Title
Pharmacokinetics(the duration of survival of cells in vivo)
Description
Duration of BZ019 persistence is the period from the day of infusion to the first negative test result. It aims to calculate the area under the plasma concentration versus time curve (AUC)
Time Frame
Month 24
Title
Pharmacodynamics
Description
Pharmacodynamics is defined as the level of Cytokine, at least include IL-2, IL-4, IL-6, IL-10, IL-15, IFN-γ, TNF-α. The peak value of cytokines and their return to baseline were evaluated
Time Frame
After 28 days of single infusion
Title
Antitumor efficacy-Objective response rate (ORR)
Description
The number of cases in which tumor size is reduced to PR or CR / the total number of evaluable cases (%)
Time Frame
Month 24
Title
Antitumor efficacy-Overall survival (OS)
Description
The period from the first infusion to any cause of death
Time Frame
Month 24
Title
Antitumor efficacy-Progression-free survival (PFS)
Description
The period from the day when the subject receives the infusion of cells to the first recorded tumor progression (whether treated or not) or death of any cause, which occurs first.
Time Frame
Month 24
Title
Antitumor efficacy-event -free survival (EFS)
Description
Event free survival rate refers to the time from enrollment to occurrence of any event, including death, disease progression, change of chemotherapy program, change to chemotherapy, additional treatment, occurrence of lethal or intolerable side effects and other events.
Time Frame
Month 24
Title
Antitumor efficacy- Tumor progression time (TTP)
Description
Tumor progression time refers to the time from the beginning of the infusion of cells to tumor progression
Time Frame
Month 24

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, only DLBCL non-specific type, primary mediastinal large B-cell lymphoma, follicular lymphoma transformed large B-cell lymphoma, advanced B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement, advanced B-cell lymphoma non-specific type. The definition of refractory is as follows: no response to the last treatment, including:The best response to the latest treatment is disease progression (PD), or the best response to the latest treatment plan is disease stability (SD) and the maintenance time is not more than 6 months after the last administration; or not suitable for autologous hematopoietic stem cell transplantation (ASCT), or ASCT refractory, including: disease progression after ASCT or recurrence within ≤ 12 months (recurrence must be confirmed by biopsy), or if receiving remedial treatment after ASCT, the subject must have no reaction or recurrence after the last treatment. Subjects must be accepted adequate treatment before and have received at least 2 lines of treatment or relapse or progress after autologous hematopoietic stem cell transplantation, and the treatment history at least include: Treatment by CD20 monoclonal antibody (Rituximab) except for CD20 negative; a chemotherapy regimen containing anthracyclines. According to the preliminary evaluation, staging and response evaluation recommendations for Hodgkin and non Hodgkin's lymphoma (2014 Edition), at least one measurable lesion was found in the screening period. Life expectancy ≥12 weeks. Baseline Eastern Cooperative Oncology Group (ECOG) score is 0 or 1 . Adequate organ function: Renal function defined as:A serum creatinine of ≤1.5 x ULN or Estimated Glomerular Filtration Rate (eGFR) ≥ 60 mL/min/1.73 m^2; Liver function defined as:Alanine Aminotransferase (ALT) ≤ 5 x ULN;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) ≥ 50%, confirmed by echocardiogram or Multigated Radionuclide Angiography (MUGA). No blood transfusion within 1 week before signing the informed consent, sufficient bone marrow reserve is available, which is defined as: Absolute neutrophil count (ANC) > 1000/μl; Absolute lymphocyte count (ALC) ≥ 500/μl; Platelets ≥ 50000/μl; Hemoglobin > 8.0 g/dl, for patients with bone marrow invasion, hemoglobin > 6.0 g/dl can be considered into the group. Must have an apheresis product of non-mobilized cells accepted for manufacturing. If the patient uses the following drugs, the following conditions should be met: glucocorticoids: The treatment dose of glucocorticoids must be stopped 72 hours before BZ019 infusion. However, glucocorticoids of physiological alternative dose are allowed: prednisone or its equivalent ≤ 15 mg / day; 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 age and all male subjects must agree to use effective contraceptive methods until BZ019 are no longer present in the body (detected by PCR). Exclusion Criteria: Patients who have previously received any anti-CD45, anti-CD19 or anti-CD3 therapy; Patients who have previously received any adoptive T cell therapy or gene therapy products, including CAR-T 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. 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 6 weeks of infusion. Patients with positive hepatitis B (HBsAg and / or HBcAb positive, except for those with positive surface antibody alone) or hepatitis C serological markers; HIV positive or Treponema pallidum positive patients. Patients with uncontrollable active or life-threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours before infusion); Patients with unstable angina and / or myocardial infarction within 6 months before screening, or patients with serious or uncontrollable other diseases (such as unstable or uncompensated respiratory, heart, liver or kidney diseases) during 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. Patients with uncontrolled arrhythmia. Patients on oral anticoagulation therapy within 1 week prior to BZ019 infusion. Patients with active neurological auto immune or inflammatory disorders(e.g. Guillain Barre Syndrome, Amyptrophic Lateral Sclerosis) Other protocol-related inclusion/exclusion may apply.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Yan Sun, M.D
Phone
021-59593168
Email
suny@shcell.org
First Name & Middle Initial & Last Name or Official Title & Degree
Zhicai Lin, M.D
Phone
021-59593168
Email
linzc@shcell.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lugui Qiu, Ph.D
Organizational Affiliation
Hematology Hospital, Chinese Academy of Medical Sciences
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hematology Hospital, Chinese Academy of Medical Sciences
City
Tianjin
ZIP/Postal Code
300020
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lugui Qiu, prof.
Phone
022-23909282
Email
qiulg@ihcams.ac.cn
Facility Name
Tianjin medical university cancer institute and hospital
City
Tianjin
ZIP/Postal Code
300060
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lanfang Li, prof.
Phone
022-23340123
Ext
3210
Email
lilanfangmeng@163.com

12. IPD Sharing Statement

Plan to Share IPD
No

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Study of Safety and Efficacy of BZ019 in (R/R) Large B-cell Lymphoma

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