IASO207 Injection in the Treatment of Relapsed/Refractory B-cell Malignancies

This study is a single-arm, single-center, open-label First-in-Human clinical trial (FIH), aiming to preliminarily evaluate the safety and efficacy of IASO207 injection in patients with Relapsed/Refractory B-cell Malignancies,and to determine the recommended dose for subsequent clinical trials. The "3+3" dose-escalation design was adopted in the dose-escalation stage, and three dose-escalation dose groups of 5.0×10^8 TU, 1.0×10^9 TU and 2.0×10^9 TU were preset. Each dose group level included 3-6 subjects with a single dose. The objective is to preliminarily observe the safety and tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of IASO207 injection at different doses in patients with Relapsed/Refractory B-cell Malignancies and provide evidence for subsequent clinical trials.

Inclusion criteria

• 1. Age ≥ 18 years old and ≤ 75 years old.
• 2. Previously diagnosed by histopathological biopsy as one of the following pathological types:

• Diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS); high-grade B-cell lymphoma (HGBL);
• DLBCL transformed from indolent lymphoma, including transformation from follicular lymphoma (FL) or marginal zone lymphoma (MZL), and DLBCL transformed from CLL/SLL (Richter transformation);
• Grade 3B follicular lymphoma (FL3B); primary mediastinal large B-cell lymphoma (PMBCL).
• 3. Recurrent/refractory B-cell lymphoma patients who have failed standard treatment (including recurrence, non-response, progression) must have received a standard immunotherapy regimen containing CD20 monoclonal antibody and anthracycline drugs:

• Recurrent disease refers to the occurrence of disease recurrence or progression ≥ 12 months after treatment;
• Refractory disease refers to disease progression during treatment or best response of disease stability (SD), or recurrence within 12 months after autologous hematopoietic stem cell transplantation, or disease progression within 12 months after treatment.
• 4. Before enrollment, it is confirmed that CD19 target expression is positive:

• Previous pathological results indicate positive CD19 expression, and/or;
• Can provide archived or fresh puncture specimens to the central laboratory for detection to confirm positive CD19 expression.
• 5. According to the Lugano 2014 standard, there is at least one measurable lesion (lymph node lesion LDi > 1.5 cm, extranodal lesion LDi > 1.0 cm);( LDi is longest diameter)
• 6. ECOG score 0-2;
• 7. Expected survival period ≥ 12 weeks;
• 8. Screening period examination confirms appropriate organ function: i. Blood routine: absolute neutrophil count (ANC) ≥ 1×109/L; platelets (PLT) ≥ 50×109/L; hemoglobin (Hb) ≥ 70g/L (must not have received any G-CSF/GM-CSF treatment or red blood cell and platelet transfusion within 7 days before laboratory examination); ii. Peripheral blood T lymphocyte absolute count ≥ 300 cells/μL; iii. Liver function: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5× upper limit of normal (ULN); serum total bilirubin ≤ 1.5× ULN (for patients with tumor liver metastasis: ALT/AST ≤ 5× ULN; TBil ≤ 3× ULN); iv. Cardiac function: left ventricular ejection fraction (LVEF) ≥ 50%; v. Pulmonary function: oxygen saturation at rest ≥ 91%; vi. Renal function: calculated creatinine clearance rate (CrCl) ≥ 40 ml/min according to Cockcroft-Gault formula; vii. Coagulation function: fibrinogen ≥ 1.0g/L; activated partial thromboplastin time (aPTT) ≤ 1.5× ULN, prothrombin time (PT) ≤ 1.5× ULN;
• 9. Pregnant participants should agree to take effective contraceptive measures or drugs from the date of signing the informed consent form until at least 1 year after the last administration of IASO207 injection.

Exclusion criteria

• 1. There is invasion of central nervous system tumors; and/or primary central nervous system DLBCL, primary testicular LBCL.
• 2. The tumor involves the small intestine, colon, and/or imaging examination indicates that the tumor involves the sub-mucosal layer of the gastrointestinal tract, and the patient has been evaluated to have a risk of organ perforation.
• 3. Within the past 5 years before screening, the subject has had other malignant tumors except for the disease under study, excluding cervical carcinoma in situ after radical treatment, basal cell or squamous cell skin cancer after radical treatment, local prostate cancer, breast duct carcinoma in situ or thyroid papillary carcinoma.
• 4. Infectious disease screening meets one of the following conditions: i. The subject has positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and abnormal peripheral blood HBV DNA test (abnormal HBV DNA test is defined as: HBV DNA quantitative test higher than the detection center's lower limit or higher than the normal reference range of the detection center or HBV DNA qualitative test positive); ii. The subject has positive hepatitis C virus (HCV) antibody and positive peripheral blood HCV RNA; iii. The subject has positive human immunodeficiency virus (HIV) antibody; iv. The subject has syphilis; v. The subject is an active CMV infection patient.
• 5. Before enrollment, there is uncontrollable active bacterial, fungal or viral infection: i. There are persistent symptoms/signs related to infection that require intravenous anti-infection drug treatment; ii. After appropriate anti-infection treatment, the clinical symptoms and examinations do not indicate improvement.
• 6. Severe heart disease: including but not limited to unstable angina pectoris, myocardial infarction (within 6 months before screening), congestive heart failure (NYHA functional classification standard ≥ III), severe arrhythmia.
• 7. Within the past 6 months before screening, the subject has had central nervous system diseases or histories, such as epilepsy, paralysis, aphasia, cerebral infarction, cerebral hemorrhage, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome (such as cerebral aneurysm, epilepsy, stroke [except lacunar infarction], senile dementia, psychosis, etc.) or patients with consciousness disorders.
• 8. The subject has received any CD19-targeted treatment before.
• 9. The subject has received any allogeneic hematopoietic stem cell transplantation (Allo-HSCT), autologous CAR-T and other allogeneic donor cell adoptive therapy.
• 10. The subject with a large mass (diameter of the lesion > 7.5 cm) is not included in this study; patients whose disease progresses too rapidly and is expected not to benefit from the treatment of this study will not be included in this study.
• 11. Before enrollment, the subject does not meet the drug/treatment washout period: i. The subject needs or is continuously using systemic corticosteroids or other immunosuppressants within 4 weeks before enrollment; ii. The subject has received bispecific antibody, autologous hematopoietic stem cell transplantation, autologous CAR-T treatment within 12 weeks before enrollment; iii. The subject has received radiotherapy or grade 4 major surgery within 4 weeks before enrollment; or plans to undergo general anesthesia surgery within 12 weeks after receiving the study treatment.

iv. Using monoclonal antibodies, cytotoxic chemotherapy, or ADC drugs within 4 weeks prior to enrollment; v. Having received vaccination or any off-label clinical study drug treatment within 4 weeks prior to enrollment.

• 12. Judged by the investigator, there are other unstable systemic diseases: including but not limited to severe liver, kidney or metabolic diseases that require treatment.
• 13. The adverse reactions caused by previous anti-tumor treatment have not been alleviated to ≤ grade 2 (NCI-CTCAE v5.0 version).
• 14. Those with a history of allergic reactions to the excipient components of IASO207 injection.
• 15. Those who have received solid organ transplantation in the past.
• 16. Pregnant or lactating women.
• 17. Other situations deemed by the investigator as not suitable for enrollment.