Overview

The study is a Phase II, single-arm, open-label, single-dose clinical trial, and its primary objective is to evaluate the efficacy and safety of CNCT19 Cell Injection in the treatment of relapsed or refractory NHL.

Eligibility

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 treatment

   requirements

   1. 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 stem

      cell 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-line adequate therapy or progressive disease (PD), and SD after a second-line therapy for at least 2 cycles or PD .
   3. In relapsed or refractory status at screening:
      • Definition of relapse: Remission (including partial remission (PR) or complete remission (CR)) after treatment with at least the standard therapy 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 SD or
             PD; Relapse or progression after ASCT, including: Relapse (it must be proved by
             biopsy) or PD within 12 months after ASCT; if a rescue therapy is received, the
             patient is non-responsive (SD or PD) to the last therapy;
             For transformed follicular lymphoma (TFL), patients must be treated adequately against
             FL, and after transformation, must have received at least once the therapy against
             TFL, and become relapsed or refractory after the last therapy.
          4. Measurable imaging lesion at screening: Intranodal lesion must have a long diameter of
             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 hepatic
             dysfunction due to tumor cell infiltration): Aspartate aminotransferase (AST) ≤ 3
             Upper Limit of Normal (ULN); Alanine aminotransferase (ALT) ≤ 3 ULN; Total serum
             bilirubin ≤ 2 ULN, unless there exists concurrent Gilbert syndrome; patients with
             Gilbert 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 thromboplastin
             time (aPTT) ≤ 1.5 ULN.
          8. Vascular conditions for apheresis;
          9. Women with child-bearing potential are negative in blood/urine pregnancy tests within
             3 d prior to apheresis, and prior to infusion of CNCT19 cell injection infusion; any
             male or female patient with child-bearing potential must agree to adopt effective
             contraceptive measures throughout the study, and at least a year after administration
             of the investigational therapy. As judged by the investigator, a patient with
             child-bearing potential means that: He/she has normal sexual life and is biologically
             fertile to have children. Non-fertile female patients (i.e., complying one of the
             following criteria):Previously received hysterectomy, bilateral ovariectomy, or
             bilateral tubal ligation, or Medically confirmed ovarian failure, or Medically
             confirmed postmenopause (amenorrhea of at least 12 consecutive months).
        Exclusion Criteria:
          1. Patients with active central nervous system (CNS) lymphoma (a patient with CNS disease
             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 central
             nervous 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 autoimmune disease
             involved with central nervous system.
          3. Patients receiving any of the following drugs or therapies within the specified period
             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 more than
                  3 half-lives prior to apheresis is eligible;
               -  Non-lymphocytotoxic chemotherapy within 7 d prior to apheresis - use in more than
                  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 PET
                  positive lesion at other non-radiotherapy site is eligible; if there is existing
                  PET positive lesion in other non-radiotherapy sites, then it is allowable to
                  conduct radiotherapy at a single lesion within 2 weeks prior to apheresis.
          4. Patients receiving chemotherapy within 2 weeks prior to CNCT19 Cell injection
             infusion, excluding the following conditions:
               -  Pretreatment chemotherapy as specified by the protocol;
               -  CNS lymphoma prophylaxis by intrathecal injection (it must be stopped within 1
                  week prior to infusion of CNCT19 Cell Injection).
          5. Discontinuation of a systematic therapeutic hormone within 72 h prior to infusion of
             CNCT19 Cell Injection; however, use of the hormone in the physiological surrogate
             amount 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 cell
             transplantation (allo-HSCT).
          8. Patients with known active or uncontrolled synstemic autoimmune disease and under
             treatment.
          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, anti-treponemia pallidum antibody
             (TP-Ab) positive, EBV-DNA, and CMV-DNA copies being more than the lower limit of
             detection.
         10. Patients who received a major surgery within 4 weeks prior to screening, and are not
             eligible 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 ejection fraction
             (LVEF) ≤45% (ECHO); New York Heart Association (NYHA) Grade III or IV congestive heart
             failure; Uncontrolled hypertension (systolic blood pressures≥140mmHg and/or diastolic
             blood pressures ≥90 mmHg), pulmonary hypertension, or unstable angina pectoris;
             Myocardial infarction or bridging or stent procedure within 12 months prior to
             administration of the drug; Clinically significant 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 vascular compression)
             requiring treatment, due to existing lymphoma body obstruction or compression at
             screening.
         15. Patients with active hemorrhage at screening.
         16. Patients with deep vein thrombosis within 6 months prior to screening, or a history of
             pulmonary embolism.
         17. Patients who are known with a history of hypersensitivity reaction to any ingredient
             used 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 receiving
             treatment of an active investigational drug within 3 half-lives prior to CNCT19 Cell
             Injection infusion.