Clinical Trial of ssCART-19 Cell Injection in the Treatment of Relapsed or Refractory Acute Lymphoblastic Leukemia (Including Central Nervous System Infiltration)

Phase Ⅱ Clinical Trial of ssCART-19 Cell Injection in the Treatment of CD19 Positive Relapsed or Refractory Acute Lymphoblastic Leukemia (Including Central Nervous System Infiltration)

This study is a Phase II, single-arm, open-label, non-randomized, dose-escalation clinical trial to evaluate the efficacy and safety of ssCART-19 Cell Injection in the treatment of patients with CD19 positive Relapsed or Refractory acute lymphoblastic leukemia, including central nervous system infiltration.

This study is a Phase II, single-arm, open-label, non-randomized, dose-escalation clinical trial to evaluate the efficacy and safety of ssCART-19 Cell Injection in the treatment of patients with CD19 positive Relapsed or Refractory acute lymphoblastic leukemia, including central nervous system infiltration. The study consists of screening period (8 weeks), treatment period (4 weeks), and follow-up period. All subjects who have received ssCART-19 infusion will be followed for safety and efficacy up to 2 years.

Inclusion Criteria:

1. Informed consent is signed by the subject.
2. Age 18 to 65.
3. Relapsed or refractory acute lymphoblastic leukemia (ALL), According to the Chinese Guidelines for the Diagnosis and Treatment of Acute Lymphoblastic Leukemia in Adults (2021) those who need to fulfill one of the following conditions: (1)refractory leukemia: failure to reach CR/CRi after standard induction therapy (generally referred to as the 4-week regimen or Hyper-CVAD regimen). (2) Recurrence of leukemia: patients who have already reached CR have primitive cells in their peripheral blood or bone marrow (proportion>5%). (3)Patients with Ph+ ALL are eligible if they do not reach CR after at least two lines of TKI therapy or relapse after CR (except those who are intolerant to TKI therapy, have contraindications to TKI therapy or have T315i mutations). (4)Relapse after autologous or allogeneic hematopoietic stem cell transplantation(HSCT).
4. Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening (morphological examination)
5. CD19 tumor expression demonstrated in bone marrow by flow cytometry
6. Eastern cooperative oncology group (ECOG) performance status of 0 to 1.
7. Adequate organ function at screening defined as: a.Left ventricular ejection fraction ≥ 50% by echocardiogram. b.Creatinine ≤1.5× upper limit of normal (ULN), or creatinine clearance ≥ 60 mL/min (Cockcroft and Gault). c.ALT and AST≤3×ULN, total bilirubin ≤2×ULN. d.dyspnea (CTCAE v5.0) ≤ grade 1 (shortness of breath during moderate activity) and blood oxygen saturation > 91% without oxygen inhalation as determined by investigators.
8. Vascular conditions for apheresis.
9. Females of childbearing potential who have a negative pregnancy test by blood human chorionic gonadotropin (HCG) (immunofluorescence) during the screening period and who agree to use effective contraception for at least 1 year after the infusion; male subjects whose partner is a female of childbearing potential must agree to use an effective barrier method of contraception for at least 1 year after the infusion and to refrain from sperm donation
10. The estimated survival time is more than 3 months

Exclusion Criteria:

1. Isolated extra-medullary disease relapse (except central nervous system infiltration).
2. Presence of other tumors that have not been eradicated within 5 years prior to screening that the investigator assesses may have a potential impact on the tumor.
3. Has past or at screening CNS diseases other than this disease, such as epilepsy, cerebrovascular ischemia/hemorrhage, dementia, cerebellar diseases or any CNS-related autoimmune diseases.
4. Has had treatment with any prior anti-CD19 therapy, except for leukemia cells with a positive proportion of CD19 ≥80%.
5. Therapeutic systemic doses of hormone were stopped < 72 hours prior to apheresis. However, the following physiological replacement doses of hormone are allowed: < 10 mg/day prednisone or equivalent amounts of other steroid hormones.
6. Received donor lymphocyte infusion (DLI) within 6 weeks prior to ssCART-19 infusion
7. Radiotherapy before ssCART-19 infusion:Non-CNS site of radiation completed < 2 weeks prior to ssCART-19 Infusion; CNS directed radiation completed < 8 weeks prior to ssCART-19 infusion.
8. Has had treatment with any anti-T cell antibody therapy within 4 weeks prior to monocyte collection.
9. Patients complying with any of hepatitis B surface antigen (HBsAg) and/or hepatitis B e antigen (HBeAg) positive, hepatitis B e antibody (HBe-Ab) and/or hepatitis B core antibody (HBc-Ab) positive and HBV-DNA copies being more than the lower limit of detection, hepatitis C antibody (HCV-Ab) positive, and HCV-DNA copies being more than the lower limit of detection, anti-treponemia pallidum antibody (TP-Ab) positive, human immunodeficiency virus (HIV) antibody positive, EBV-DNA, and CMV-DNA copies being more than the lower limit of detection.
10. Patients with active infections or uncontrolled infections that required systemic treatment in screening (except for mild genitourinary infections and upper respiratory infections).
11. Prior to signing the informed consent, have had cardiac angioplasty or stent placement within 12 months, or have had III-IV congestive heart failure (NYHA), or have had myocardial infarction, unstable angina, or other heart disease determined by the investigator to be ineligible for enrollment within 6 months, or QTc interval ≥480ms (QTc interval calculated by Fridericia formula) during screening, Hypertension that has not been controlled after standard treatment (systolic ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg) or pulmonary hypertension.
12. Patients have systemic diseases as judged by investigators to be unstable: including, but not limited to, severe liver, kidney, or metabolic diseases requiring medical treatment.
13. Patients with active or uncontrolled autoimmune disease, primary or secondary immunodeficiency.
14. Has had severe immediate hypersensitivity reaction to any drug to be used in this study.
15. Has had treat with live vaccine within 6 weeks prior to screening.
16. Pregnant or lactating women.
17. A history of autoimmune diseases (e. g., Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus) requiring systemic immunosuppressive/systemic disease modifying medications within the past 2 years
18. Patients with a history of allogeneic hematopoietic stem cell transplantation within 12 weeks prior to apheresis, acute graft-versus-host disease (GVHD) or moderate to severe chronic GVHD within 4 weeks prior to screening; Patients who received systemic drug therapy for GVHD within 4 weeks prior to infusion.
19. Participating in any other study and have received any other investigational drug within 4 weeks prior to screening.
20. Patients with other conditions making the patients unsuitable for this study as judged by the investigator.