Phase II Clinical Trial of CNCT19 Cell Injection in the Treatment of Relapsed or Refractory Non-Hodgkin's Lymphoma

Inclusion Criteria:

1. Patients who are willing to sign the informed consent form;

2. Aged 18-75 years, male or female;

3. At screening, subjects complying with the following diagnostic and treatmentrequirements:

4. Complying with CD19-positive NHL according to the WHO classification 2017,which are provided specifically as follows:

• Diffuse large B cell lymphoma (DLBCL), not otherwise specified (NOS);
• Primary mediastinal large B cell lymphoma (PMBCL);
• Transformed follicular lymphoma
• High grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements,and high grade B cell lymphoma - not otherwise specified.

2. Previously received≥2nd-line adequate therapy or autologous hematopoietic stemcell transplantation (ASCT), including:

• Received at least Rituximab or other CD20 targeted drugs containing (except CD20 negative tumors) chemotherapy and
• Received at least one chemotherapy regimen containing anthracycline;
• Definition of line: Stable disease (SD) after receiving a first-lineadequate therapy or progressive disease (PD), and SD after a second-linetherapy for at least 2 cycles or PD .

3. In relapsed or refractory status at screening:

• Definition of relapse: Remission (including partial remission (PR) orcomplete remission (CR)) after treatment with at least the standardtherapy regimen (it must contain Ribuximab), and then PD;
• Definition of refractoriness: Non-responsiveness to the last therapy: The best response by the last therapy is SDor PD; Relapse or progression after ASCT, including: Relapse (it must be proved bybiopsy) or PD within 12 months after ASCT; if a rescue therapy is received, thepatient is non-responsive (SD or PD) to the last therapy; For transformed follicular lymphoma (TFL), patients must be treated adequatelyagainst FL, and after transformation, must have received at least once the therapyagainst TFL, and become relapsed or refractory after the last therapy.

4. Measurable imaging lesion at screening: Intranodal lesion must have a long diameterof more than 1.5 cm, and extranodal lesion must have a long diameter of more than 1.0 cm (per revised IWG Response Criteria 2014 in Lymphomas);

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;

6. Adequate bone marrow reserve, defined as:

• Absolute neutrophil count (ANC) > 1.0×109/L;

• Absolute lymphocyte count (ALC) ≥ 0.3×109/L;

• Platelet (PLT) ≥50×109/L;

7. Proper organ function, complying with the following criteria (except hepaticdysfunction due to tumor cell infiltration): Aspartate aminotransferase (AST) ≤ 3Upper Limit of Normal (ULN); Alanine aminotransferase (ALT) ≤ 3 ULN; Total serumbilirubin ≤ 2 ULN, unless there exists concurrent Gilbert syndrome; patients withGilbert syndrome, with total serum bilirubin ≤ 3 ULN and direct bilirubin ≤ 1.5 ULN,may be included; Renal function: serum creatinine ≤ 1.5 ULN or creatinine clearance ≥ 60 mL/min (Cockcroft-Gault formula); Minimum pulmonary reserve, defined as Grade ≤ 1 dyspnea, and blood oxygen saturation > 91% at non-oxygen inhalation status;International normalized ratio (INR) ≤ 1.5 ULN and activated partial thromboplastintime (aPTT) ≤ 1.5 ULN.

8. Vascular conditions for apheresis;

9. Women with child-bearing potential are negative in blood/urine pregnancy testswithin 3 d prior to apheresis, and prior to infusion of CNCT19 cell injectioninfusion; any male or female patient with child-bearing potential must agree toadopt effective contraceptive measures throughout the study, and at least a yearafter administration of the investigational therapy. As judged by the investigator,a patient with child-bearing potential means that: He/she has normal sexual life andis biologically fertile to have children. Non-fertile female patients (i.e.,complying one of the following criteria):Previously received hysterectomy, bilateralovariectomy, or bilateral tubal ligation, or Medically confirmed ovarian failure, orMedically confirmed postmenopause (amenorrhea of at least 12 consecutive months).

Exclusion Criteria:

1. Patients with active central nervous system (CNS) lymphoma (a patient with CNSdisease symptoms must receive lumbar puncture and MRI/CT to exclude CNS lymphoma).

2. Patients with existing central nervous system disease or with a history of centralnervous system disease, e.g., epileptic seizure, cerebral ischemia/hemorrhage,paralysis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease,cerebellum disease, organic brain syndrome, mental disease, or any autoimmunedisease involved with central nervous system.

3. Patients receiving any of the following drugs or therapies within the specifiedperiod prior to apheresis:

• Alemtuzumab within 6 months prior to apheresis;

• Cladribine within 3 months prior to apheresis;

• Anti-CD20 monoclonal antibody within 7 d prior to apheresis;

• Venetoclax (BCL-2 inhibitor) within 4 d prior to apheresis;

• Idelalisib (PI3Kδ kinase inhibitor) within 2 d prior to apheresis;

• Lenalidomide within 1 d prior to apheresis;

• Lymphocytotoxic chemotherapy within 2 weeks prior to apheresis - use in morethan 3 half-lives prior to apheresis is eligible;

• Non-lymphocytotoxic chemotherapy within 7 d prior to apheresis - use in morethan 3 half-lives prior to apheresis is eligible;

• Radiotherapy within 6 weeks prior to apheresis, including big bone marrow area (e.g., sternum or pelvis) - progressive disease at radiotherapy site, or PETpositive lesion at other non-radiotherapy site is eligible; if there isexisting PET positive lesion in other non-radiotherapy sites, then it isallowable to conduct radiotherapy at a single lesion within 2 weeks prior toapheresis.

4. Patients receiving chemotherapy within 2 weeks prior to CNCT19 Cell injectioninfusion, excluding the following conditions:

• Pretreatment chemotherapy as specified by the protocol;

• CNS lymphoma prophylaxis by intrathecal injection (it must be stopped within 1week prior to infusion of CNCT19 Cell Injection).

5. Discontinuation of a systematic therapeutic hormone within 72 h prior to infusion ofCNCT19 Cell Injection; however, use of the hormone in the physiological surrogateamount is eligible (e.g., Prednisone in a dose of <10 mg/d or equivalent).

6. Patients previously received CAR-T cell therapy.

7. Patients who have previously received allogeneic hematopoietic stem celltransplantation (allo-HSCT).

8. Patients with known active or uncontrolled synstemic autoimmune disease and undertreatment.

9. Patients complying with any of hepatitis B surface antigen (HBsAg) and/or hepatitisB e antigen (HBeAg) positive, hepatitis B e antibody (HBe-Ab) and/or hepatitis Bcore antibody (HBc-Ab) positive and HBV-DNA copies being more than the lower limitof detection, hepatitis C antibody (HCV-Ab) positive, anti-treponemia pallidumantibody (TP-Ab) positive, EBV-DNA, and CMV-DNA copies being more than the lowerlimit of detection.

10. Patients who received a major surgery within 4 weeks prior to screening, and are noteligible for enrollment as judged by the investigator.

11. Patients with concurrent active malignancy; those with a history of malignancy,cured for≥2 years, are eligible.

12. Patients complying any of the following conditions: Left ventricular ejectionfraction (LVEF) ≤45% (ECHO); New York Heart Association (NYHA) Grade III or IVcongestive heart failure; Uncontrolled hypertension (systolic bloodpressures≥140mmHg and/or diastolic blood pressures ≥90 mmHg), pulmonaryhypertension, or unstable angina pectoris; Myocardial infarction or bridging orstent procedure within 12 months prior to administration of the drug; Clinicallysignificant valvular heart disease; Other heart diseases unsuitable for enrollment,as judged by the investigator.

13. Patients with lymphoma involved with atrium or ventricle.

14. Patients with clinical emergency (e.g., intestinal infarction or vascularcompression) requiring treatment, due to existing lymphoma body obstruction orcompression at screening.

15. Patients with active hemorrhage at screening.

16. Patients with deep vein thrombosis within 6 months prior to screening, or a historyof pulmonary embolism.

17. Patients who are known with a history of hypersensitivity reaction to any ingredientused for the drug product in the trial.

18. Patients vaccinated with a live vaccine within 6 weeks prior to screening.

19. Patients with active infection at screening.

20. Patients with a life expectancy of less than 3 months.

21. Patients participating in any other interventional clinical study or receivingtreatment of an active investigational drug within 3 half-lives prior to CNCT19 CellInjection infusion.