Relapsed or Refractory B Cell Leukemia and Lymphoma
Conditions
Brief summary
This study is a single-arm, open-label clinical investigation to evaluate the tolerance, safety and preliminary efficacy of CAR-T (U96) in the treatment of relapsed/refractory B-cell tumors. The study will be conducted in two disease types, acute B-lymphoblastic leukemia and B-cell lymphoma, with a dose escalation plan using the "3+3" method. Each dose group is planned to enroll 3 to 6 patients, with a total of approximately 30 to 48 patients to be enrolled in the entire study. After signing the informed consent form, patients will undergo screening tests. If they meet the inclusion and exclusion criteria, they will be enrolled in the study. After receiving U96 treatment, patients will be followed up. It is recommended that they stay in the hospital for at least 14 days after administration. Safety and efficacy follow-ups will be conducted at 28 days and 3, 6, 12, 18, and 24 months after treatment. The follow-up period after treatment will last for 2 years, with a long-term follow-up of 15 years to assess the efficacy and safety until the end of the study or the patient withdraws from the study. For patients who have received U96 treatment, even if they withdraw from the study early, the investigators should still conduct long-term safety follow-ups according to the protocol to evaluate the long-term safety of the product.
Interventions
DRUGU96
U96(CD7-targeted lentiviral vector for in vivo production of IL-6 knockdown CD19 CAR)
Sponsors
The First Affiliated Hospital of Soochow University
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* (All the following items must be met simultaneously) 1. Patients must voluntarily sign the informed consent form and have good compliance; 2. For different indications, patients must meet the following requirements: 2-1) Patients in the acute B lymphoblastic leukemia group: 1. The age at signing the informed consent form is ≥ 18 years old, both male and female are acceptable; 2. According to the standards of the National Comprehensive Cancer Network (NCCN) Acute Lymphoblastic Leukemia Clinical Practice Guidelines (2024, 2nd Edition), it is clearly diagnosed as acute B lymphoblastic leukemia; 3. According to the "Chinese Adult Acute Lymphoblastic Leukemia Diagnosis and Treatment Guidelines" (2021 Edition), one of the following conditions must be met: a. Refractory leukemia: standard induction therapy fails to achieve CR/CRi after (generally referring to 4-week regimen or Hyper-CVAD regimen) completion; b. Leukemia recurrence: patients who have achieved CR have peripheral blood or bone marrow with blast cells (proportion \> 5%) or MRD positive or extramedullary lesions; 2-2) Patients in the B-cell lymphoma group: <!-- --> 1. The age at signing the informed consent form is ≥ 18 years old, both male and female are acceptable; 2. According to the standards of the National Comprehensive Cancer Network (NCCN) B-cell lymphoma clinical practice guidelines (2024, 3rd Edition), it is clearly diagnosed as B-cell lymphoma; 3. Patients with B-cell lymphoma who have failed at least two-line treatment (one standardized chemotherapy regimen + one salvage chemotherapy) or have relapsed before screening. The previous treatment of B-cell lymphoma must include CD20 monoclonal antibody (excluding CD20-negative tumor patients) and anthracycline-based standardized treatment regimen. At least one of the following conditions must be met: a. Unable to undergo autologous hematopoietic stem cell transplantation; b. Refuse to undergo autologous hematopoietic stem cell transplantation; c. Relapse after autologous hematopoietic stem cell transplantation; 4. At screening, the patient is in a state of disease recurrence or refractory: a) Recurrence definition: after adequate treatment achieving remission (including partial remission (PR) or complete remission (CR)), PD again occurs; b) Refractoriness definition: i. No response to the last treatment: PD during/after the last treatment or the best efficacy is SD, and the duration is less than 6 months; ii. Recurrence or progression after ASCT (requiring biopsy confirmation), including: recurrence or PD within 12 months after ASCT, if salvage treatment is received, no response (SD or PD) to the last treatment; 3. Bone marrow or peripheral blood or immunohistochemistry or pathology shows CD19 antigen positive; 4. According to the Lugano Lymphoma Response Evaluation Criteria (Cheson 2014), B-cell lymphoma patients have at least one evaluable lesion, or positive lesions confirmed by PET-CT; 5. Eastern Cooperative Oncology Group (ECOG) performance status score is 0-3; 6. At screening, there is a certain degree of bone marrow reserve, defined as: absolute lymphocyte value (ALC) ≥ 0.3×109/L, platelet (PLT) ≥ 30×109/L (allowing the result after administration); 7. Have appropriate organ function, and need to meet the following standards: aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal (ULN); alanine aminotransferase (ALT) ≤ 3 times ULN (for liver function abnormalities caused by tumor infiltration, AST and ALT ≤ 5 times ULN are required); total serum bilirubin The serum bilirubin should be ≤ 2 times the ULN, except for those with Gilbert syndrome who have a combined condition; the total bilirubin should be ≤ 3 times the ULN and the direct bilirubin should be ≤ 1.5 times the ULN. Patients with Gilbert syndrome who meet these criteria can be included. The serum creatinine should be ≤ 1.5 times the ULN, or the creatinine clearance rate should be ≥ 60 mL/min (Cockcroft and Gault formula); possess the lowest level of pulmonary reserve, defined as ≤ 1 grade of dyspnea and a blood oxygen saturation \> 91% in non-oxygenated state; left ventricular ejection fraction of the left heart in echocardiography should be ≥ 50%; International Normalized Ratio (INR) should be ≤ 1.5 times the ULN, and activated partial thromboplastin time (APTT) should be ≤ 1.5 times the ULN; 8. The blood/urine pregnancy test for women of childbearing age during the screening period should be negative. Any male or female patient with reproductive capacity must agree to use an effective contraceptive method throughout the study process and for at least 1 year after the administration of the study treatment; 9. The expected survival period should be greater than 3 months.
Exclusion criteria
* (Any of the following conditions will disqualify one from participating) 1. Having another malignant tumor and the investigator considers that the presence of other malignant tumors may affect the current treatment; 2. Any of the following conditions: positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBc-Ab), and the HBV-DNA copy number is greater than the minimum detection limit; positive for hepatitis C antibody (HCV-Ab), and the HCV-RNA copy number is greater than the minimum detection limit; positive for anti-mycoplasma antibody (TP-Ab); positive for human immunodeficiency virus (HIV) antibody; 3. Existing bacterial, fungal, viral, mycoplasma or other types of infections and the investigator determines that they are difficult to control; 4. Having a CNS disease other than this disease in the past or currently, such as epileptic seizures, cerebral ischemia/hemorrhage, dementia, cerebellar disease or any CNS-related autoimmune disease, and the investigator determines that it is uncontrollable; 5. Before signing the informed consent form, having undergone cardiac angioplasty or stent placement within 12 months, or having NYHA classification III-IV grade congestive heart failure, or having myocardial infarction, unstable angina pectoris or the investigator determines that there is a clinically significant history of heart disease, or the patient's QTc interval is \> 480 ms (QTc interval calculated using the Fridericia formula), and the left ventricular ejection fraction of the heart ultrasound is \< 50%; 6. Patients with primary immunodeficiency; 7. Having had a severe immediate-type hypersensitivity reaction to any drug used in this study; 8. Having received live vaccines within 6 weeks before screening; 9. Pregnant or lactating women; 10. Active autoimmune diseases; 11. Having active acute or chronic graft-versus-host disease (GVHD) at the time of signing the informed consent form, and the investigator determines that it is uncontrollable; 12. Participating in any other interventional clinical research within 30 days before signing the informed consent form; 13. Situations that the investigator deems unsuitable for participating in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-limiting toxicity (DLT) | Within 28 days after U96 infusion | Description: DLT refers to any of the following conditions occurring within 28 days after cell reinfusion that are related to cell infusion: ① Hematologic DLT: Grade 4 toxicity (excluding lymphopenia) not caused by the underlying disease and taking more than 30 days to resolve to ≤ Grade 2. ② Non-hematologic DLT: Any toxicity ≥ Grade 4 that is possibly related to CAR-T therapy, or Grade 3 toxicity that requires ≥7 days to resolve to ≤ Grade 2 or to return to baseline. |
| Adverse Event (AE） | 2 years | Description: Record the types, occurrence frequency and severity of adverse events (AEs) related to CAR-T, with specific definitions determined according to CTCAE v5.0.The CRS and ICANS ratings do not use CTCAE but adopt the evaluation criteria in the ASTCT standards. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 28 days and within 3 months after infusion of U96 | The acute B lymphocytic leukemia group is defined as the proportion of patients who achieved complete remission (CR), complete remission with incomplete hematological recovery (CRh), and complete remission with incomplete bone marrow recovery (CRi); the B-cell lymphoma group is defined as the complete remission rate (CR) and partial remission (PR) as determined by the investigators. |
| MRD-negative rate (for B-ALL) | 28 days and within 3 months after infusion of U96 | The proportion of B-ALL patients with negative MRD in the bone marrow when the therapeutic effect reaches remission. B-ALL patients have residual leukemia cells in the bone marrow detected by flow cytometry below 10-⁴ and/or negative qualitative or quantitative detection of bone marrow fusion genes (if any).MRD is detected by CD19 flow cytometry immunophenotyping (bone marrow). |
| Duration of Response (DOR) | 2 years | It refers to the time from the evaluation of CR/CRh/CRi in patients with acute B-cell leukemia, or from the time when patients with B-cell lymphoma first reach response (CR or PR) to disease recurrence/disease progression/death due to disease.Subjects who have not experienced disease progression or death by the time of the final data collection will be censored at the time of their last valid tumor assessment. Common reasons for censoring include, but are not limited to: ①Loss to follow-up; ②Withdrawal from the study; ③Initiation of a new anticancer therapy. |
| Best Overall Response (BOR) | 2 years | The Best Overall Response is defined as the proportion of patients who achieve the best response (CR or CRi) after study treatment.The review period extends from the start of infusion of U96 until the initiation of subsequent anti-cancer therapy, disease progression, withdrawal of consent, death, or study closure, whichever comes first. |
| Overall Survival (OS) | 2 years | Defined as the time from the date of cell infusion to the date of death from any cause. For subjects who are still alive at the time of analysis, OS will be censored on the date of last known contact. |
| Progression-Free Survival (PFS) | 2 years | The duration from the start of the treatment to the onset of disease progression or death for patients with B-cell lymphoma. For patients who did not experience disease progression or death by the analysis cutoff date, the last tumor evaluation time was used for censored processing. |
| Relapse-Free Survival (RFS) | 2 years | Defined as the time from the start of study treatment to the date of first documented relapse in patients with B-cell acute lymphoblastic leukemia (B-ALL). |
| Event-Free Survival (EFS) | 2 years | Defined as the time from the date of cell infusion to the occurrence of any of the following events (whichever comes first): ①Death from any cause after achieving remission ②Disease relapse or progression ③Treatment failure, defined as either lack of efficacy or discontinuation of the clinical trial due to: -Death -Adverse events -Lack of efficacy or disease progression -Initiation of new antitumor therapy |
| Pharmacokinetics-AUC(0-28) | 2 years | The area under the curve from 0 to 28 days for the reinfusion. |
| Pharmacokinetics-Cmax | 2 years | The peak concentration of the drug in the peripheral blood sample. |
| Pharmacokinetics-Tmax | 2 years | The time at which the peak concentration of the drug is reached in the peripheral |
| IL-6 | Within 28 days after U96 infusion | Changes in the levels of IL-6 |
| Ferritin | Within 28 days after U96 infusion | Changes in the levels of Ferritin |
| C-reactive protein(CRP) | Within 28 days after U96 infusion | Changes in the levels of CRP |
| Pharmacokinetics-Proportion of B cells. | Within 28 days after U96 infusion | Change from baseline in peripheral blood B cell ratio |
Countries
China
Contacts
CONTACTSheng-Li Xue
Outcome results
None listed