A Clinical Trial of CNCT19 Cells in the Treatment of CD19 Positive Relapsed or Refractory Acute Lymphoblastic Leukemia

This is a single arm, open-label, non-randomized, dose-escalation, phase I study to determine the safety and efficacy of CNCT19 in adult patients with relapsed or refractory acute lymphoblastic leukemia. The study will have the following sequential phases: Screening, Pre-Treatment (Cell Product Preparation & Lymphodepleting Chemotherapy), Treatment and Follow-up, and Survival Follow-up. The total duration of the study is 2 years from CNCT19 cell infusion.

Inclusion criteria

• Informed consent is signed by the subject.
• Age 18 to 65.
• Relapsed or refractory ALL

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

• aspartate aminotransferase (AST) ≤ 3 upper limit of normal (ULN);
• Serum alanine aminotransferase (ALT) ≤ 3 upper limit of normal (ULN);
• 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;
• A serum creatinine≤ 1.5 ULN or Creatine removal rate ≥ 60mL/min (Cockcroft and Gault);
• Must have a minimum level of pulmonary reserve as ≤ Grade 1 dyspnea and oxygen saturation > 91% on room air;
• International normalized ratio (INR) ≤ 1.5 ULN and activated partial thromboplastin time (APTT) ≤ 1.5 ULN.
• Have appropriate vascular conditions for apheresis.
• Non-hematological toxic reactions (excluding diseases related) caused by previous treatment were restored to ≤ 1 level before screening (excluding ≤ 2 level of neurotoxicity caused by hair loss and chemotherapy drugs).
• Women of childbearing age have a negative blood / urine pregnancy test within 7 days before 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 six months after the CNCT19 infusion.

Exclusion criteria

• Active CNS involvement by malignancy.
• Isolated extra-medullary disease relapse.
• Patients who received chemotherapy within 2 weeks before CNCT19 infusion. The following situations are excluded:

• Lymphodepleting Chemotherapy prescribed by the protocol;
• Tyrosine kinase inhibitors (TKI) and hydroxyurea must be stopped > 72 hours prior to CNCT19 infusion;
• 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;
• Pegylated-asparaginase must be stopped > 4 weeks prior to CNCT19 infusion;
• CNS prophylaxis treatment must be stopped > 1 week prior to CNCT19 infusion.
• 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.

• 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.
• Has had treatment with any prior CAR-T therapy.
• Patients who have previously received allogeneic hematopoietic stem cell transplantation (allo-HSCT).
• Patients with systemic vasculitis (such as Wegener granulomatosis, nodular polyarteritis, systemic lupus erythematosus) and active or uncontrolled autoimmune disease (such as autoimmune hemolytic anemia, etc.).
• Patients who are positive for any of HBsAg, HBeAg, HBeAb, HBcAb, HCV-Ab, TP-Ab.
• Active malignancy. Patients with Prior malignancy that has been cured for ≥ 2 years are excluded.
• a. Left Ventricular Ejection Fraction (LVEF) ≤45%; b. III/IV congestive heart failure (NYHA); c. Severe arrhythmia ; QTc≥450ms (male)or QTc≥470ms (female)(QTcB=QT/RR1/2); d.Uncontrolled hypertension (systolic blood pressure ≥140 mmHg and / or diastolic blood pressure ≥90 mmHg) or pulmonary hypertension or unstable angina; e. 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.
• Clinically significant pleural effusion.
• Patients with a history of epilepsy, cerebrovascular ischemia / hemorrhage, cerebellar disease or other active central nervous system diseases.
• History of deep vein thrombosis or pulmonary embolism within 6 months of screening.
• Known history of hypersensitivity to ingredients used in the drug.
• Has had treat with live vaccine within 6 weeks prior to screening.
• Patients with evidence of currently uncontrollable serious active infections (e.g., sepsis, bacteremia, fungemia, viremia, etc.).
• Life expectancy < 3 months.
• Patient in other interventional clinical studies within 3 months before screening, who have received active drug therapy, or who intend to participate in another clinical trial or receive anti-tumor therapy outside the protocol during the entire study.
• Patients with other conditions making the patients unsuitable for receiving cell therapy as judged by the investigator.