A Clinical Study Exploring the Safety, Efficacy and Cell Metabolic Kinetics of Universal Car-t Cell Injection in CD19 and / or CD20 Positive Relapsed / Refractory B-cell Acute Lymphoblastic Leukemia in Adolescents, Children and Adults

A Clinical Study Exploring the Safety, Efficacy and Cell Metabolic Kinetics of Universal Car-t Cell Injection in CD19 and / or CD20 Positive Relapsed / Refractory B-cell Acute Lymphoblastic Leukemia in Adolescents, Children and Adults

This study is a single arm, open label, dose exploring clinical trial to evaluate the safety, efficacy, cellular metabolic dynamics, and pharmacodynamics of ct1190b cells in relapsed / refractory B-cell acute lymphoblastic leukemia.

The study was divided into dose escalation phase and dose expansion phase. It is planned to enroll 18-36 study participants.

The participants were divided into two treatment groups. Group A was adult participants ≥ 18 years old who received ct1190b treatment. The dose escalation was tentatively determined at three dose levels: dl1:3.0 × 10^8, dl2:4.5 × 10^8, dl3:6.0 × 10^8 car-t cells. ， Group B consisted of 12-17-year-old adolescents and children. The dose escalation was tentatively defined as two dose levels. Dl1:3.0 × 10^6 /kg car-t cells, the maximum total number of infused cells was not more than 1.5 × 10^8 car-t cells, dl2:6.0 × 10^6 /kg car-t cells, the maximum total number of infused cells was not more than 3.0 × 10^8 car-t cells. The dose escalation of the two groups followed the "i3+3" design. It was planned to enroll 18-36 study participants. At the dose escalation stage, all patients of different subtypes were mixed into the group. Without distinguishing between groups, the dose escalation of group A was given priority. After obtaining certain data, the dose escalation of group B was performed (fig.it can receive other research data of the same indication of this product). If the starting dose of group A (3.0 × 10^8) meets the dose reduction standard according to the i3+3 principle (the i3+3 decision table indicates "d" or "Du", refer to the incremental decision table of the i3+3 principle for details), the investigator and the funder will jointly discuss and decide whether to enter the decreasing dose of 1.5 × 10^8. If the maximum dose currently set is not confirmed as the possible recommended dose (RD), the investigator and the funder can jointly decide whether to increase it to a higher dose to explore the possible recommended therapeutic dose. During the study, the dose group may be increased or decreased or the dose may be extended according to the safety, effectiveness and cellular metabolic dynamics data of the study participants.

Inclusion Criteria:

• voluntarily participate in clinical research; I fully understand and know this study and sign the informed consent form; ;

• aged 12-75 years (inclusive);

• relapsed / refractory B-ALL diagnosed by morphology, immunology or molecular science, and meeting one of the following conditions:

  1. The patients who did not achieve complete remission by the standardized induction chemotherapy, or early relapse (<12 months) after complete remission, or late relapse (≥ 12 months) after complete remission, and did not achieve complete remission by the standardized one course induction chemotherapy (except for the patients with late relapse who did not have a better treatment or did not tolerate other treatments according to the investigator's assessment), relapsed after 2 or more CR or CRI;
  2. For ph+all patients, in addition to receiving standard induction chemotherapy, they should also receive at least two kinds of TKI treatment without complete remission or relapse after complete remission (except those who cannot tolerate TKI treatment or have contraindications to TKI treatment, or those with T315I mutation do not need to receive TKI treatment);

• CD19 and / or CD20 positive in bone marrow or peripheral blood;

• the proportion of bone marrow cell morphology or peripheral blood suggestive blasts ≥ 5%;

• estimated survival >12 weeks;

• study participants should meet the following inspection results (there should be no ongoing continuous supportive care):

  1. Endogenous creatinine clearance ≥ 30 ml/min (using Cockcroft Gault formula);
  2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN, total bilirubin ≤ 1.5 × ULN; In case of hepatobiliary invasion: AST and alt ≤ 5 × ULN, total bilirubin ≤ 3.0 × ULN;
  3. International normalized ratio (INR) and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN;
  4. Oxygen saturation in non oxygen inhalation state was > 91%;
  5. Left ventricular ejection fraction (LVEF) ≥ 50%.

• Male study participants who had active sex with women with reproductive potential were willing to use very effective and reliable methods of contraception within 1 year after receiving study treatment. All male study participants were absolutely forbidden to donate sperm within 1 year after receiving study treatment infusion during the study period.

Exclusion Criteria:

• pregnant or lactating women;

• there is HIV, syphilis infection, active hepatitis B virus infection (HBV-DNA is higher than the detection limit), or active hepatitis C virus infection (both HCV antibody and HCV-RNA are positive);

• there is currently any uncontrollable active infection, including but not limited to patients with active tuberculosis (judged by the investigator);

• there is active systemic autoimmune disease;

• patients with solitary extramedullary lesions;

• research participants with a history of neurological diseases, such as epilepsy, intracranial hemorrhage, severe brain injury, cerebellar disease, memory impairment, spinal cord compression or any disease involving the central nervous system, or suspected active central nervous system (CNS) metastasis;

• patients with bone marrow failure status related genetic syndromes: such as Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Patients with Down syndrome were not excluded.

• for patients who relapsed after treatment with drugs targeting CD19 and / or CD20 before screening, the investigator judged that they could not benefit; 10. have received stem cell transplantation within 12 weeks before signing the informed consent; Received donor lymphocyte infusion (DLI) within 6 weeks;

• received the following treatments before cell infusion:

  1. Received anthracyclines, vinblastines, 6-mercaptopurine, 6-thioguanine, methotrexate, cytarabine, asparaginase, etc. within 7 days before infusion;
  2. Hydroxyurea and tyrosine kinase inhibitors were used within 3 days before infusion;
  3. Radiotherapy was used within 1 week before infusion (2 weeks interval for lung radiotherapy and 8 weeks interval for CNS radiotherapy);
  4. CNS prophylactic therapy (such as intrathecal injection of chemotherapeutic drugs) within 1 week before infusion;
  5. Give any T-cell lysis or antibody (such as alemtuzumab) within 8 weeks before infusion;
  6. Use monoclonal antibody, double antibody or ADC within 4 weeks before infusion;
  7. ;
  8. Received systemic glucocorticoids equivalent to >15 mg/ day prednisone within 3 days before infusion, except for glucocorticoids used locally;
  9. Polyethylene glycol asparaginase was used within 4 weeks before infusion;

• have been vaccinated with live attenuated vaccine, inactivated vaccine or RNA vaccine within 4 weeks before signing the informed consent;

• those who are allergic or intolerant to Qinglin drugs and tocilizumab, or allergic to components (dimethyl sulfoxide /dmso) in ct1190b cell infusion preparations; Or previous history of other serious allergies such as anaphylactic shock;

• patients with any of the following cardiac diseases before screening:

  1. New York Heart Association (NYHA) class III or IV heart failure;
  2. ;
  3. A history of clinically significant uncontrolled arrhythmias, such as ventricular arrhythmias;
  4. A history of severe non ischemic cardiomyopathy;
  5. Other heart diseases that the investigator believes may endanger the health of the patient due to participation in this clinical study;

• serious lung disease may endanger the patient's life after participating in the study as judged by the investigator;

• there are second primary malignant tumors that need treatment or have not been completely relieved in the past 2 years, except the following successfully treated tumors with low malignancy such as non metastatic basal cell carcinoma or squamous cell skin carcinoma, non metastatic prostate cancer, breast cancer or cervical cancer in situ, non muscle invasive bladder cancer or thyroid cancer;

• major surgery within 2 weeks before signing the informed consent, or major surgery planned during the study or within 4 weeks after giving the study treatment (excluding cataract and other local anesthesia surgery);

• after organ transplantation;