Safety of Autologous Humanized Anti-CD19 and Anti-CD20 Dual Specific CAR-T Cells in Adult Patients With Diffuse Large B-cell Lymphoma

  • STATUS
    Recruiting
  • End date
    Dec 28, 2024
  • participants needed
    18
  • sponsor
    Fujian Medical University
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Updated on 19 February 2024
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Summary

This is a single-arm, open-label, dose escalation, phase I study, aiming to evaluate the safety and efficacy of Autologous Humanized Anti-CD19 and Anti-CD20 Dual Specific Chimeric Antigen Receptor (CAR) T-cells in patient with relapsed or refractory diffuse B cell lymphoma.

Description

CD19 CAR-T cell therapy has made breakthroughs in the treatment of B cell lymphoma and leukemia, but 30% of patients still have antigen escape, which may be related to variants in tumor cells and the expansion of CD19-negative tumor cells after treatment with CD19 CAR-T cells. CD19/CD20 bispecific CAR-T cell targeting multiple antigens can attack tumor cells while overcoming tumor antigen escape caused by a single target, maximizing efficacy and duration of treatment, and can also solve the problem of uneven distribution or low expression of single target on the tumor surface.

Details
Condition Relapsed or Refractory DLBCL Patients With Either CD19 or CD20 Positive
Age 18-100 years
Treatment Autologous humanized anti-CD19 and anti-CD20 dual specific CAR-T Cells
Clinical Study IdentifierNCT04215016
SponsorFujian Medical University
Last Modified on19 February 2024

Eligibility

 Yes No Not Sure

Inclusion Criteria

The subject or her/his legally guardian(s) must sign the informed consent form approved by the Institutional Ethics Committee (IEC) prior to any screening procedures
Subjects aged 18 years or older with relapsed or refractory DLBCL (primary mediastinal large B-cell lymphoma and transformed follicular lymphoma included), of which refractory is defined as
Have no response to the recent treatment including
The best response to the treatment regimen is progressive disease (PD) ,or
stable disease (SD) which maintained less than 6 months after the last treatment, or
not suitable for autologous hematopoietic stem cell transplantation (ASCT), or ASCT refractory, including
progressive disease after ASCT or relapse within 12 months (relapse must be confirmed by biopsy), or
If remedial treatment is given after ASCT, the subject must have no response or relapse after the last treatment. 3\. Subjects who have previously received 2 lines treatment, and at least including
Anti-CD20 monoclonal antibody(rituximab), unless the CD20 negative
A chemotherapy regimen containing anthracyclines
The DLBCL patients who transformed from follicular lymphoma must have previously received chemotherapy for follicular lymphoma and have developed chemotherapy-refractory diseases after transform to DLBCL. 4\. Confirmation for either CD19 or CD20 positivity using immunohistochemistry or flow cytometry; 5\. According to the initial evaluation, staging and response assessment of Hodgkin's and non-Hodgkin's lymphoma -the Lugano Classification (2014), there is at least one measurable lesion at baseline; 6\. Life expectancy 12 weeks; 7\. Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1 at screening; 8\. Adequate organ function
Renal function defined as
A serum creatinine of 1.5 Upper Limit of Normal (ULN), or
Estimated Glomerular Filtration Rate (eGFR) 60 ml/min/1.73m2
Liver function defined as
ALT 5 Upper Limit of Normal (ULN) for age, and
Total 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 ULN and direct bilirubin 1.5 ULN
Must have a minimum level of pulmonary reserve defined as Grade 1 dyspnea and
blood oxygen saturation > 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) >110^9 /L
Absolute lymphocyte count (ALC) 0.310^9 /L
Platelets 5010^9 /L
Hemoglobin > 8.0 g/dl; 11\. Must have an apheresis product of non-mobilized cells or peripheral blood harvested cells accepted for manufacturing 12\. Subjects who use the following drugs should meet the following criteria
Steroids: Therapeutic doses of steroids must be stopped 2 weeks prior to A-02 infusion. However, the following physiological replacement doses of steroids are allowed: < 6 - 12 mg/m^2/day hydrocortisone or equivalent
Immunosuppression: Any immunosuppressive medication must be stopped 4 weeks prior to sign the informed consent form
Anti-proliferative therapy other than pretreatment chemotherapy within 2 weeks of A-02 infusion
CD20 antibody-related treatment must be discontinued within 4 weeks of A-02 infusion or 5 half-lives (whichever is longer)
CNS disease prophylaxis must be stopped > 1 week prior to A-02 infusion (e.g. intrathecal methotrexate); 13\. The investigator judged that the subject recovered from the toxicity of the previous anti-tumor treatment to grade 1 or below (except for special grade 2 or below toxicity that cannot be recovered in a short period of time, such as hair loss), suitable for pretreatment. Chemotherapy and treatment of CAR-T cells; 14\. Women of child-bearing potential and all male subjects must agree to use highly effective methods of contraception for at least 12 months following A-02 infusion and until CAR-T cells are no longer present by PCR on two consecutive tests

Exclusion Criteria

Prior treatment with any cell therapy before signing the informed consent form, including CAR-T therapy
Subjects with detectable cerebrospinal fluid malignant cells or brain metastases, or with a history of central nervous system (CNS) lymphoma or primary CNS lymphoma
Subjects with testicular invasion, including those who have had testicular resection
Subjects with current or previous history of central nervous system disease, such as seizures, cerebral ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease involving the central nervous system
Subjects who have previously received allogeneic hematopoietic stem cell transplantation (HSCT); or suitable and consenting to Autologous hematopoietic stem cell transplantation (ASCT)
Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of A-02 infusion
Patients on oral anticoagulation therapy within 1 week of A-02 infusion
Prior radiation therapy within 2 weeks of A-02 infusion
Investigational medicinal product within the last 30 days prior to sign the informed consent form
Subjects with active hepatitis Bdefined as hepatitis B surface antigen positive, or hepatitis B core antibody positive with hepatitis B virus DNA detection value > 1000 copies/mlor hepatitis C (HCV RNA positive)
Subjects positive for HIV antibody or treponema pallidum antibody
Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive 72 hours prior to A-02 infusion)
Unstable angina and/or myocardial infarction within 6 months prior to sign the informed consent form
Previous or concurrent malignancy with the following exceptions
Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to sign the informed consent form)
In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to sign the informed consent form
A primary malignancy which has been completely resected and in complete remission for 5 years
Pregnant or nursing women (women of childbearing age were tested positive for pregnancy during screening period)
Cardiac arrhythmia not controlled with medical management
Subjects with active neurological auto immune or inflammatory disorders (e.g. Guillain Barre Syndrome, Amyotrophic Lateral Sclerosis)
Other conditions that the investigator thinks he/she should not be included in this clinical trial, such as poor compliance
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