Clinical Trial of CNCT19 Cell Injection in the Treatment of Relapsed or Refractory Acute Lymphoblastic Leukemia

Inclusion Criteria:

1. Informed consent is signed by the subject.
2. Age 18 to 65.
3. Relapsed or refractory acute lymphoblastic leukemia (ALL). (1) Relapse within 12 months of first remission; (2)a. Without remission after more than 6 weeks of induction chemotherapy or without remission after 2 cycles of induction chemotherapy regimen; c. 2nd or greater Bone Marrow (BM) relapse OR; d. First relapse after chemotherapy, without remission after at least 1 rescue treatment; e. Any BM relapse after autologous or allogeneic stem cell transplantation (SCT).
4. Documentation of CD19 tumor expression demonstrated in bone marrow or peripheral blood within 3 months of study entry.
5. Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are intolerant to or have failed 2 generation of tyrosine kinase inhibitor therapy (TKI); no TKI salvage treatments if the patient has a T315I mutation.
6. Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening.
7. Eastern cooperative oncology group (ECOG) performance status of 0 to 1.
8. Adequate organ function defined as:

   1. aspartate aminotransferase (AST) ≤ 3 upper limit of normal (ULN);
   2. Serum alanine aminotransferase (ALT) ≤ 3 upper limit of normal (ULN);
   3. Total bilirubin ≤ 2 ULN, except in individuals with Gilbert's syndrome; Note: Patients with Gilbert's syndrome that bilirubin ≤ 3 ULN and direct bilirubin ≤ 1.5 ULN will be eligible;
   4. A serum creatinine≤ 1.5 ULN or Creatine removal rate ≥ 60mL/min (Cockcroft and Gault）;
   5. Must have a minimum level of pulmonary reserve as ≤ Grade 1 dyspnea and oxygen saturation \> 91% on room air;
   6. International normalized ratio (INR) ≤ 1.5 ULN and activated partial thromboplastin time (APTT) ≤ 1.5 ULN.
9. Vascular conditions for apheresis.
10. Women of childbearing age have a negative blood / urine pregnancy test within 3 days before apheresis and the CNCT19 infusion. Women of child-bearing potential and all male participants must use highly effective methods of contraception throughout the study and for a period of at least two years after the CNCT19 infusion.

Exclusion Criteria:

1. Active Central Nervous System (CNS) involvement by malignancy.
2. Isolated extra-medullary disease relapse.
3. Patients who received chemotherapy within 2 weeks before CNCT19 infusion. The following situations are excluded:

   1. Lymphodepleting Chemotherapy prescribed by the protocol;
   2. Tyrosine kinase inhibitors (TKI) and hydroxyurea must be stopped \> 72 hours prior to CNCT19 infusion;
   3. The following drugs must be stopped \> 1 week prior to CNCT19 infusion: 6-mercaptopurine, 6-thioguanine, methotrexate (\<25 mg / m2), cytosine arabinoside (\<100 mg / m2 / d), vincristine, asparaginase;
   4. CNS prophylaxis treatment must be stopped \> 1 week prior to CNCT19 infusion;
   5. Pegylated-asparaginase must be stopped \> 4 weeks prior to CNCT19 infusion.
4. Radiotherapy before CNCT19 infusion:

   Non-CNS site of radiation completed \< 2 weeks prior to CNCT19 Infusion; CNS directed radiation completed \< 8 weeks prior to CNCT19 infusion.
5. Therapeutic systemic doses of steroids were stopped \< 72 hours prior to CNCT19 infusion. However, the following physiological replacement doses of steroids are allowed: \< 10 mg/day hydrocortisone or equivalent.
6. Has received anthracycline/anthraquinone drug treatment exceeding the maximum cumulative dose recommended by the guidelines, estimated by investigators before screening, as follows:

   * Doxorubicin: 550mg/m2 (radiotherapy or combined medication, \<(radiotherapy or combined medication, \<350\~400 mg/m2);
   * Epirubicin: 900\~1000 mg/m2 (Adriamycin used, \<800 mg/m2);
   * Pirarubicin: 950 mg/m2;
   * Daunorubicin: 550 mg/m2;
   * Demethoxydaunorubicin: 290 mg/m2;
   * Aclarithromycin: 2000 mg/m2 (Adriamycin used, \<800 mg/m2);
   * Mitoxantrone: 160 mg/m2 (using doxorubicin, \<120 mg/m2);
7. Has had treatment with any prior CAR-T therapy.
8. Patients with acute graft-versus-host disease (GVHD) or moderate-to-severe chronic GVHD within 4 weeks before screening; Patients who have received systemic drug therapy for GVHD within 4 weeks before CNCT19 infusion.
9. Patients with systemic vasculitis.
10. 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, anti-treponemia pallidum antibody (TP-Ab) positive, EBV-DNA, and CMV-DNA copies being more than the lower limit of detection.
11. Prior malignancy. Patients with Prior malignancy that has been cured for ≥ 5 years or has a low risk of relapse, judged by investigators are excluded.
12. a. Left Ventricular Ejection Fraction (LVEF) ≤45%; b. III/IV congestive heart failure (NYHA); c. Severe arrhythmia, or clinically significant conduction abnormalities that can be seen on ECG, including QTc interval ≥480ms (QTcB=QT/RR1/2); d. Hypertension that has not been controlled after standard treatment (systolic ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg); e. Unstable angina; f. Myocardial infarction or Coronary Artery Bypass Graft Surgery, heart stent surgery \< 6 months prior to CNCT19 infusion; f. Clinically significant valvular disease; g. Other heart diseases that have been judged by the investigator to be unsuitable for receiving cell therapy.
13. Clinically significant pleural effusion.
14. Patients with a history of epilepsy, cerebrovascular ischemia / hemorrhage, cerebellar disease or other active central nervous system diseases.
15. History of deep vein thrombosis or pulmonary embolism within 6 months of screening.
16. Known history of hypersensitivity to ingredients used in the drug.
17. Has had treat with live vaccine within 6 weeks prior to screening.
18. Patients with active infections in screening.
19. Life expectancy \< 3 months.
20. Patient in other interventional clinical studies, who received live investigational product, including: Unlisted new drugs within 3 months before CNCT19 injection, marketed drug within 5 half-lives before CNCT19 injection, or who intend to participate in another clinical trial or receive anti-tumor therapy outside the protocol during the entire study.
21. Patients with other conditions making the patients unsuitable for receiving cell therapy as judged by the investigator.