A Clinical Trial of CNCT19 Cells in the Treatment of CD19 Positive Relapsed or Refractory Diffuse Non-Hodgkin Lymphoma
A Clinical Trial of CNCT19 Cells in the Treatment of CD19 Positive Relapsed or Refractory Diffuse Non-Hodgkin Lymphoma
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 diffuse
 Non-Hodgkin lymphoma.
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 diffuse
 Non-Hodgkin lymphoma. 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:

 1. Informed consent is signed by the subject.

 2. Age 18 to 75.

 3. Relapsed or refractory NHL with CD19-positive after at least two systemic lines of
 therapy

 a. Diffuse large B cell lymphoma (DLBCL) non-specific (NOS), T-cell / Histiocyte Rich
 large B-cell lymphoma, elderly EBV-positive diffuse large B-cell lymphoma, primary
 mediastinal large B-cell lymphoma (PMBCL), chronic inflammation-associated DLBCL,
 follicular lymphoma (FL) transformed large B-cell lymphoma, high-grade B-cell lymphoma
 with MYC and BCL2 and / or BCL6 rearrangement and High-grade B-cell
 lymphoma-unspecified; b. Chemotherapy-refractory disease, defined as one of more of
 the following:

 -  No response to last line of therapy; i. Progressive disease (PD) as best response
 to most recent therapy regimen; ii. Stable disease (SD) as best response to at
 least 4 courses of first-line treatment / at least 2 courses of end-line
 treatment (2 lines and above) with duration no longer than 6 month from last dose
 of therapy OR;

 -  Refractory post-autologous stem cell transplant (ASCT); i. Disease progression or
 relapsed less than or equal to 12 months of ASCT (must have biopsy proven
 recurrence in relapsed individuals); ii. If salvage therapy is given post-ASCT,
 the individual must have had no response to or relapsed after the last line of
 therapy; Any BM relapse after autologous stem cell transplantation (ASCT); c.
 Individuals must have received two systemic lines of therapy

 -  anti-CD20 monoclonal antibody unless investigator determines that tumor is
 CD20-negative;

 -  an anthracycline containing chemotherapy regimen;

 -  FL-transformed DLBCL must have received pre-chemotherapy for FL and become
 resistant after conversion to DLBCL.

 4. At least one measurable lesion, defined as at least 1 lymph node >1.5 cm in the
 longest diameter, per revised IWG Response Criteria.

 5. Any previous systemic immune checkpoint therapy (such as anti-PD1 / PD-L1 monoclonal
 antibody, etc.), at least 3 half-lives away from the Cell Product Preparation; other
 systemic treatments should be stoped at least 2 weeks or 5 half-lives before Cell
 Product Preparation (shorter Whichever comes first).

 6. Eastern cooperative oncology group (ECOG) performance status of 0 to 1.

 7. Sufficient bone marrow reserves defined as:

 1. Absolute neutrophil (ANC) > 1,000 / mm3;

 2. Lymphocyte absolute value (ALC) ≥ 100 / mm3;

 3. Platelet (PLT) ≥ 50,000 / mm3.

 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. 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).

 10. 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:

 1. Active CNS involvement by malignancy.

 2. Patients who received chemotherapy within 2 weeks before CNCT19 infusion. The
 following situations are excluded:

 1. Lymphodepleting Chemotherapy prescribed by the protocol;

 2. CNS prophylaxis treatment must be stopped > 1 week prior to CNCT19 infusion.

 3. Has had treatment with any prior anti-CD19 therapy.

 4. Plans to receive autologous stem cell transplantation (ASCT) within 6 weeks before the
 CNCT19 infusion.

 5. Patients who have previously received Allogeneic Hematopoietic Stem Cell
 Transplantation (allo-HSCT).

 6. 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.).

 7. Patients who are positive for any of HBsAg, HCV-Ab, TP-Ab.

 8. Patients who have previously received surgery within 4 weeks before the screening that
 was unsuitable for enrollment by the investigator's assessment.

 9. Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative
 intent and with no evidence of active disease. Patients with Prior malignancy that has
 been cured for ≥ 2 years are excluded.

 10. a. Left Ventricular Ejection Fraction (LVEF) ≤45%; b. III/IV congestive heart failure
 (NYHA); c. Severe arrhythmia (except for Atrial fibrillation, Paroxysmal
 supraventricular tachycardia); d. QTc≥450ms (male)or QTc≥470ms
 (female)(QTcB=QT/RR1/2); 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.

 11. Clinically significant pleural effusion.

 12. Patients with a history of epilepsy, cerebrovascular ischemia / hemorrhage, cerebellar
 disease or other active central nervous system diseases.

 13. Lymphoma affects the atrium or ventricle.

 14. Clinical emergencies (such as intestinal obstruction or vascular compression) that
 requires urgent treatment due to obstruction or compression of lymphoma tumors during
 screening.

 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 evidence of currently uncontrollable serious active infections (e.g.,
 sepsis, bacteremia, fungemia, viremia, etc.).

 19. Life expectancy < 12 weeks.

 20. Patient in other interventional clinical studies within 3 months before the CNCT19
 infusion, 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.

 21. Patients with other conditions making the patients unsuitable for receiving cell
 therapy as judged by the investigator.