Relapsed or Refractory DLBCL Patients With Either CD19 or CD20 Positive Clinical Trial
— A-02Official title:
A Single-arm, Open-label, Dose Escalation Study to Explore Safety, Efficacy and Pharmacokinetics of Autologous Humanized Anti-CD19 and Anti-CD20 Dual Specific CAR-T Cells in Adult Patients With Relapsed or Refractory Diffuse Large B Cell Lymphoma
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.
| Status | Recruiting |
| Enrollment | 18 |
| Est. completion date | December 2024 |
| Est. primary completion date | December 2023 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility |
Inclusion Criteria: 1. 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; 2. 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; 9. Hemodynamically stable and Left Ventricle Ejection Fraction (LVEF) = 45% confirmed by echocardiogram or Multigated Radionuclide Angiography (MUGA); 10. Adequate bone marrow reserve without transfusions defined as: - Absolute neutrophil count (ANC) >1×10^9 /L; - Absolute lymphocyte count (ALC) =0.3×10^9 /L; - Platelets =50×10^9 /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: 1. Prior treatment with any cell therapy before signing the informed consent form, including CAR-T therapy; 2. Subjects with detectable cerebrospinal fluid malignant cells or brain metastases, or with a history of central nervous system (CNS) lymphoma or primary CNS lymphoma; 3. Subjects with testicular invasion, including those who have had testicular resection; 4. 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; 5. Subjects who have previously received allogeneic hematopoietic stem cell transplantation (HSCT); or suitable and consenting to Autologous hematopoietic stem cell transplantation (ASCT); 6. Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of A-02 infusion; 7. Patients on oral anticoagulation therapy within 1 week of A-02 infusion; 8. Prior radiation therapy within 2 weeks of A-02 infusion; 9. Investigational medicinal product within the last 30 days prior to sign the informed consent form; 10. Subjects with active hepatitis B(defined as hepatitis B surface antigen positive, or hepatitis B core antibody positive with hepatitis B virus DNA detection value > 1000 copies/ml)or hepatitis C (HCV RNA positive) 11. Subjects positive for HIV antibody or treponema pallidum antibody; 12. Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive = 72 hours prior to A-02 infusion) 13. Unstable angina and/or myocardial infarction within 6 months prior to sign the informed consent form; 14. 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; 15. Pregnant or nursing women (women of childbearing age were tested positive for pregnancy during screening period); 16. Cardiac arrhythmia not controlled with medical management; 17. Subjects with active neurological auto immune or inflammatory disorders (e.g. Guillain Barre Syndrome, Amyotrophic Lateral Sclerosis); 18. Other conditions that the investigator thinks he/she should not be included in this clinical trial, such as poor compliance. |
| Country | Name | City | State |
|---|---|---|---|
| China | Fujian Medical University Union Hospital | Fuzhou | Fujian |
| Lead Sponsor | Collaborator |
|---|---|
| Fujian Medical University |
China,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | The types and Incidence of adverse events | Up to 12 months | ||
| Secondary | Overall response rate | including CR and PR | Up to 12 months | |
| Secondary | Progression-free survival (PFS) | Up to 12 months | ||
| Secondary | Response duration | Up to 12 months |