An Open-label, Single-arm, Prospective, Multicenter, Phase I/II Clinical Study on the Safety and Efficacy of CD19/BCMA CAR-T Cell Therapy for Relapsed/Refractory Warm Antibody Autoimmune Hemolytic Anemia
Overview
- Phase
- Phase 1
- Status
- Not yet recruiting
- Sponsor
- Yihao Wang
- Enrollment
- 24
- Primary Endpoint
- Incidence and Severity of Adverse Events
Overview
Brief Summary
This study is an open-label, single-arm, prospective, multicenter, phase I/II clinical trial. It adopts the two-stage optimal design proposed by Bryant and Day to investigate the efficacy, safety, and in vivo pharmacokinetic characteristics of CD19/BCMA CAR-T cell therapy in the treatment of relapsed/refractory warm antibody autoimmune hemolytic anemia.
Detailed Description
With reference to the protocol by the team led by Georg Schett from Germany, a dosage of 1×10⁶ CAR⁺ cells per kilogram was selected, and it is planned to enroll 24 subjects with relapsed/refractory warm antibody autoimmune hemolytic anemia (wAIHA).
The two-stage optimal design proposed by Bryant and Day was adopted:
Stage 1: A total of 8 participants will be enrolled, with the core objective of evaluating the tolerance to treatment-related toxicity. By monitoring safety events (including grade ≥2 cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and grade 3-4 neutropenia lasting more than 28 days, etc.), it will be determined whether the number of such events is ≤ 5.
Stage 2: A total of 16 participants will be enrolled, focusing on assessing treatment response, which requires that at least 4 participants achieve a definite therapeutic effect.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Aged ≥ 18 years and ≤ 75 years.
- •Meeting the criteria for relapsed/refractory warm antibody autoimmune hemolytic anemia (wAIHA), and the patient must have received treatment with at least one of rituximab or cyclophosphamide.
- •Criteria for diagnosing relapsed/refractory warm antibody AIHA: It refers to warm antibody AIHA in which the patient has poor response to first-line and second-line or above standard treatments (e.g., glucocorticoids), or the disease recurs after effective treatment, or the patient requires continuous or repeated treatment to control the disease.
- •Disease duration of more than 6 months, with persistent disease activity or progression despite receiving conventional treatment for ≥ 2 months, or recurrence of disease activity after disease remission. Definition of conventional treatment: Use of glucocorticoids plus at least one of the following immunomodulators: cyclophosphamide, cyclosporine, and biological agents (including rituximab, etc.).
- •No systemic active infection (e.g., infectious pneumonia, pulmonary tuberculosis) within 2 weeks before leukapheresis.
- •Expected survival time of more than 3 months from the date of signing the informed consent form.
- •Peripheral blood routine meeting the following requirements simultaneously: absolute neutrophil count (ANC) ≥ 1000/μL; hemoglobin (HGB) ≥ 60 g/L; platelet count (PLT) ≥ 30,000/μL.
- •Hepatic, renal, cardiopulmonary functions meeting the following requirements:
- •Creatinine ≤ 1.5 × upper limit of normal (ULN);
- •Left ventricular ejection fraction (LVEF) ≥ 50%;
Exclusion Criteria
- •Concomitant diagnosis of any type of tumor, which is deemed unsuitable for participation in this study by the investigator.
- •A history of clinically significant central nervous system (CNS) diseases or pathological changes caused by non-autoimmune diseases prior to screening, including but not limited to: cerebrovascular accident, aneurysm, epilepsy, convulsions/seizures, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis.
- •A history of major organ transplantation (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/bone marrow transplantation.
- •Presence of IgA deficiency at screening (serum IgA level \< 10 mg/dL).
- •Presence of any of the following conditions at screening:
- •Active hepatitis (hepatitis B virus deoxyribonucleic acid \[HBV-DNA\] or hepatitis C virus ribonucleic acid \[HCV-RNA\] test results above the lower limit of detection);
- •Human immunodeficiency virus (HIV) infection, known acquired immunodeficiency syndrome (AIDS), or syphilis infection.
- •A history of any of the following cardiovascular diseases within 6 months prior to screening: New York Heart Association (NYHA) Class III or IV heart failure, myocardial infarction, unstable angina pectoris, uncontrolled or symptomatic atrial arrhythmia, any ventricular arrhythmia, or other heart diseases with significant clinical significance.
- •Having received any of the following treatments for autoimmune diseases:a) Use of therapeutic-dose corticosteroids (defined as prednisone or its equivalent \> 20 mg/day) within 7 days before leukapheresis;b) Use of any other investigational drugs for autoimmune diseases within 4 weeks before leukapheresis, except for cases where the drug was ineffective or disease progressed during the investigational treatment, and at least 3 half-lives have passed before leukapheresis (enrollment is permitted in such cases);c) Previous receipt of CAR-T cell therapy or other genetically modified T cell therapies.
- •A history of grade ≥ 2 bleeding within 30 days before screening, or long-term continuous treatment with anticoagulant drugs (e.g., warfarin, low-molecular-weight heparin, or factor Xa inhibitors, etc.).
Arms & Interventions
CD19/BCMA CAR-T Cell Therapy for Relapsed/Refractory Warm Antibody Autoimmune Hemolytic Anemia
Intervention: CD19/BCMA CAR-T (Drug)
Outcomes
Primary Outcomes
Incidence and Severity of Adverse Events
Time Frame: Within 28 days after CAR-T infusion
Evaluate the number of cases, incidence rate, and severity of various adverse events after CD19/BCMA CAR-T infusion, mainly focusing on immunotherapy-related toxic reactions such as cytokine release syndrome (CRS), immune effector cell therapy-associated
Secondary Outcomes
- Pharmacokinetics-Tlast(Day7, Day10, Day14, Day28, Month2 , Month3 , Month6 , Month9, Month12 after treatment)
- Progression-free Survival (PFS)(Minimum of 1 years post CAR-T infusion)
- Pharmacokinetics-AUC(0~28days)(Day 7, Day10, Day 14, Day 28 after treatment)
- Overall response rate (ORR) evaluated by the investigators(Day 28, Month 3, Month 6 after treatment)
- Changes in immunological indicators and hemolysis-related indicators after infusion.(Day 28, Month 2, Month 3, Month 6, Month 12, and Month 24 after treatment)
- Pharmacokinetics-Tmax(Day 7, Day10, Day 14, Day 28 after treatment)
Investigators
Yihao Wang
Associate Chief Physician
Tianjin Medical University General Hospital