SNC116 Therapy for Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia

Inclusion criteria

• Participants must meet all of the following inclusion criteria to be enrolled in this study:

• Age ≥ 18 years and ≤ 75 years, with no gender restrictions.
• ECOG score 0 to 2.
• Diagnosed with B-ALL through MICM (cytological morphology, immunology, cytogenetics, and molecular genetics), and tested positive for CD19 by flow cytometry or immunohistochemistry.
• Recurrence or refractory B-ALL is defined as:

• Early recurrence: Recurrence occurring within 12 months after the first complete remission;
• Primary refractory: Failure to achieve complete remission after two cycles of standardized chemotherapy;
• ≥ 2 lines of systemic treatment for recurrence or refractory;
• Recurrent or refractory after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) (at least 6 months from the transplantation date to the administration date of SNC116);
• For participants with Ph-positive disease, at least 2 different TKIs must have relapsed or been refractory, or the participant must be intolerant to TKI treatment, or have a TKI treatment contraindication, or be TKI-resistant (with T315i mutation or other resistance mechanisms).
• Bone marrow morphology shows > 5% of primitive cells.
• Participants who have received targeted CD19 therapy (including monoclonal antibodies, bispecific antibodies, ADCs, CAR-NK, experimental treatments, etc.) must have CD19 expression still present after the last targeted CD19 therapy (if the CD19 expression is a quantitative result, the positive CD19 in the primitive cells must be > 90%).
• Expected survival is greater than 3 months.
• Blood routine and lymphocyte subsets within 7 days before SNC116 administration meet the following requirements:

• Absolute neutrophil count (ANC) ≥ 0.5 × 10^9/L;
• Absolute lymphocyte count (ALC) ≥ 0.5 × 10^9/L;
• Hemoglobin (Hb) ≥ 80 g/L;
• Platelet count (PLT) ≥ 50 × 10^9/L;
• CD3+ T cell absolute count ≥ 0.25 × 10^9/L.
• Adequate liver, kidney, lung, and heart function, defined as:

• Serum ALT and AST ≤ 2.5 times the upper limit of normal;
• Total bilirubin ≤ 1.5 times the upper limit of normal, except for Gilbert syndrome patients, whose total bilirubin must be ≤ 3.0 times the upper limit of normal;
• Creatinine clearance rate (estimated by Cockcroft-Gault formula) ≥ 50 ml/min;
• Saturations of blood oxygen ≥ 92% under indoor ventilation conditions without clinical significance of pleural effusion;
• Left ventricular ejection fraction ≥ 45%; Echocardiography shows no clinical significance of pericardial effusion; ECG has no clinical significance of abnormal findings.
• Participants receiving hematopoietic growth factor support therapy, including erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and platelet agonists (TPO), must have a 1-week interval between the last administration of growth factor support therapy and the screening period assessment; Participants receiving blood product transfusions must have a blood platelet assessment at least 1 week apart from the last platelet transfusion, and a blood hemoglobin assessment at least 1 week apart from the last red blood cell transfusion.
• During the screening period, serum pregnancy test results of fertile female participants must be negative (women who have undergone surgical sterilization or have been menopausal for at least 2 years are considered to have no fertility). Fertile female participants and male participants must use highly effective contraceptive methods throughout the entire clinical study period and within one year after the last study treatment; they must also commit not to donate eggs (oocytes, oocyte cells) / sperm for assisted reproduction within one year after the last study treatment.
• Participants must agree not to donate blood, organs, sperm / semen, and/or eggs after SNC116 treatment for at least one year. Currently, there is no sufficient data to confirm when donating any tissue is safe; therefore, participants should not donate any tissue after receiving SNC116.
• Voluntarily participate in the clinical trial and sign the informed consent form.

Exclusion criteria

• Participants who meet any of the following exclusion criteria will not be eligible to participate in this clinical study:

• Diagnosed with Burkitt leukemia/lymphoma or chronic myeloid leukemia with acute lymphocytic transformation according to the WHO classification.
• Recurrence with isolated extramedullary lesions.
• Within the previous 2 years, had a malignant tumor that required treatment or had evidence of recurrence (excluding: fully cured non-melanoma skin cancer, cervical carcinoma in situ, localized prostate cancer, superficial bladder cancer, breast duct carcinoma in situ, thyroid cancer, and other localized carcinomas).
• Known to have any allergic, hypersensitive, intolerant or contraindicated reaction to any component of SNC116 or the drugs used in the study (such as tocilizumab), or has previously experienced a severe allergic reaction.
• Had received any treatment using vesicular virus G glycoprotein pseudotyped virus.
• Had CNS diseases:

• (1) CNS-3; or with neurological changes CNS-2 (excluding those who have improved after treatment and are assessed by the investigator as meeting the criteria);
• (2) Had seizures, cerebrovascular accidents (ischemia/haemorrhage), dementia, mental disorders, cerebellar diseases, any autoimmune disease involving the CNS, post-reversible encephalopathy syndrome (PRES), or brain edema, etc. severe CNS disease conditions.
• Those with primary immunodeficiency or severe genetic diseases.
• Had clinically significant major cardiovascular diseases, including any of the following:

• Had myocardial infarction within 6 months before screening;
• Had unstable angina pectoris within 3 months before screening;
• Uncontrolled, clinically significant arrhythmias (such as persistent ventricular tachycardia, ventricular fibrillation, torsades de pointes);
• Mobitz II type II or III atrioventricular conduction block;
• Congestive heart failure with NYHA classification ≥ 3;
• Uncontrolled hypertension (systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 100 mmHg) or with hypertensive crisis or hypertensive encephalopathy;
• Had deep vein thrombosis or pulmonary embolism within 6 months before screening;
• Other cardiovascular diseases that were assessed by the investigator as significantly high-risk and not suitable for enrollment.
• Had ≥ 3 grade 3 gastrointestinal bleeding within the previous 1 month, a history of peptic ulcer disease, and the investigator assessed as having a risk of ≥ 3 grade 3 gastrointestinal bleeding or perforation (CTCAE 6.0).
• Had active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at the time of screening. Allowed participants to be enrolled if they had HBsAg positive and/or HBcAb positive but HBV-DNA negative, and/or HCVAb positive but HCV-RNA negative (if the research center reported reference value ranges, the normal upper limit of HBV-DNA and HCV-RNA detection was based on the detection values of each research center, and above the detection value limit was defined as "positive"; if the research center reported only "negative/positive", "positive" was based on the test report result).
• Known positive serum HIV virus antibody or history of active HIV infection, and active syphilis patients.
• Had active or latent Mycobacterium tuberculosis infection confirmed by clinical, imaging or laboratory examination during the screening period.
• Had an uncontrolled active infection that required intravenous use of antibiotics, antiviral or antifungal drugs, etc. within 7 days before SNC116 administration.
• At the time of screening, had a confirmed and requiring maintenance treatment systemic autoimmune disease or a confirmed systemic autoimmune disease in an active stage, except for: thyroid diseases assessed by the investigator as well-controlled.
• Had received the following drugs/treatments before SNC116 administration:

• Received salvage treatment (including chemotherapy, TKIs for Ph-positive ALL, and blinatumomab, etc.) within 1 week or 5 half-lives (whichever is shorter);
• Received CNS prophylactic treatment within 1 week;
• Received treatment doses of corticosteroid drugs (prednisone > 20 mg/day or equivalent doses of other steroid hormones), except for local application or prevention of allergic reactions;
• Received prophylactic treatment with short-acting oral antiretroviral drugs;
• Received local palliative radiotherapy within 2 weeks;
• Received traditional Chinese medicine with anti-tumor indications within 2 weeks;
• Received large molecule drug treatment within 3 weeks;
• Received experimental drugs/treatment (except for clear placebo-controlled groups);
• Experienced major surgery within 4 weeks;
• Received live vaccines within 4 weeks;
• Received immunosuppressants within 4 weeks;
• Used any drugs for treating GVHD (such as calcineurin inhibitors, methotrexate, mycophenolate mofetil, rapamycin, thalidomide, etc.) within 4 weeks (except for calcium channel blockers, methotrexate, mycophenolate mofetil, rapamycin, thalidomide, etc.);
• Received donor lymphocyte infusion (DLI) within 4 weeks;
• Received lymphocytotoxic drugs such as fludarabine, chlorambucil, or cladribine within 3 months, or alemtuzumab or other lymphocytotoxic drugs within 6 months;
• Received immune cell therapy such as CAR-T, CAR-NK, etc. within 3 months;
• At the time of screening, any adverse events related to previous anti-leukemia treatment that have not recovered to ≤ grade 1 or baseline level (CTCAE version 6.0) (except for alopecia, hematological toxicity related to the inclusion criteria 8, or other grade 2 adverse events that have been converted to chronic stable state by the investigator, such as alternative treatment for hypothyroidism);
• Previously received CD19 CAR-T cell therapy;
• Experienced grade 4 neurotoxicity or grade 4 cytokine release syndrome during T-cell redirected immunotherapy;
• Had any indwelling catheters or drainage tubes in the body (such as percutaneous nephrostomy tube, biliary drainage tube, or thoracic/abdominal/pericardial drainage catheter, etc.), except central venous catheterization and Ommaya reservoir;
• Had 2-4 grade acute graft-versus-host disease (GVHD) or moderate to severe chronic GVHD within 4 weeks before screening; or had acute or chronic GVHD that required systemic treatment within 4 weeks before screening;
• Pregnant or lactating women;
• Other situations that the investigator considers may affect the safety or study compliance of the participants and are not suitable for participation in the study.