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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04250324
Recruitment Status : Recruiting
First Posted : January 31, 2020
Last Update Posted : January 31, 2020
Sponsor:
Collaborators:
Institute of Hematology & Blood Diseases Hospital
Tianjin Medical University Cancer Institute and Hospital
Information provided by (Responsible Party):
Shanghai Cell Therapy Group Co.,Ltd

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.

Condition or disease Intervention/treatment Phase
Large B-cell Lymphoma Biological: BZ019 Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 21 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : November 19, 2019
Estimated Primary Completion Date : August 2022
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: BZ019
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.
Biological: BZ019
A treatment program will include lymphodepleting chemotherapy with fludarabine and cyclophosphamide (flu/cy) followed by single-dose of BZ019 administered intravenously (IV).




Primary Outcome Measures :
  1. Dose-limiting toxicity (DLT) [ Time Frame: After 28 days of single infusion ]
    Safety

  2. Maximum tolerated dose (MTD) [ Time Frame: After 28 days of single infusion ]
    Tolerability


Secondary Outcome Measures :
  1. Pharmacokinetics(the copies of cells in vivo) [ Time Frame: Month 24 ]
    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)

  2. Pharmacokinetics(the duration of survival of cells in vivo) [ Time Frame: Month 24 ]
    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)

  3. Pharmacodynamics [ Time Frame: After 28 days of single infusion ]
    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

  4. Antitumor efficacy-Objective response rate (ORR) [ Time Frame: Month 24 ]
    The number of cases in which tumor size is reduced to PR or CR / the total number of evaluable cases (%)

  5. Antitumor efficacy-Overall survival (OS) [ Time Frame: Month 24 ]
    The period from the first infusion to any cause of death

  6. Antitumor efficacy-Progression-free survival (PFS) [ Time Frame: Month 24 ]
    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.

  7. Antitumor efficacy-event -free survival (EFS) [ Time Frame: Month 24 ]
    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.

  8. Antitumor efficacy- Tumor progression time (TTP) [ Time Frame: Month 24 ]
    Tumor progression time refers to the time from the beginning of the infusion of cells to tumor progression



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04250324


Contacts
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Contact: Yan Sun, M.D 021-59593168 suny@shcell.org
Contact: Zhicai Lin, M.D 021-59593168 linzc@shcell.org

Locations
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China
Hematology Hospital, Chinese Academy of Medical Sciences Recruiting
Tianjin, China, 300020
Contact: Lugui Qiu, prof.    022-23909282    qiulg@ihcams.ac.cn   
Tianjin medical university cancer institute and hospital Recruiting
Tianjin, China, 300060
Contact: Lanfang Li, prof.    022-23340123 ext 3210    lilanfangmeng@163.com   
Sponsors and Collaborators
Shanghai Cell Therapy Group Co.,Ltd
Institute of Hematology & Blood Diseases Hospital
Tianjin Medical University Cancer Institute and Hospital
Investigators
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Principal Investigator: Lugui Qiu, Ph.D Hematology Hospital, Chinese Academy of Medical Sciences
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Responsible Party: Shanghai Cell Therapy Group Co.,Ltd
ClinicalTrials.gov Identifier: NCT04250324    
Other Study ID Numbers: XY2019028-EC-1
First Posted: January 31, 2020    Key Record Dates
Last Update Posted: January 31, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin