Overview

BEX101 injection is an extracorporeal anti-CD19 Chimeric Antigen Receptor T-Cell (CAR-T cell) therapy product. This single-arm, open-label, phase I/II clinical study is designed to evaluate the safety and efficacy of BEX101 injection in patients with relapsed or refractory (r/r) B-cell non-Hodgkin's lymphoma (NHL) .

Eligibility

Inclusion Criteria:

1. Age 18 to 75 years (inclusive), regardless of sex.
2. Subjects who meet the following diagnostic and treatment requirements:

   2.1 Any of the following B-cell non-Hodgkin lymphomas (B-NHL), confirmed by cytology or histology (according to the 2016 WHO Classification of Lymphoid Neoplasms):

   2.1.1 Diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS);

   2.1.2 Primary mediastinal large B-cell lymphoma;

   2.1.3 DLBCL transformed from follicular lymphoma (FL), or marginal zone lymphoma (MZL);

   2.1.4 High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements;

   2.1.5 FL, grades 1-3b;

   2.1.6 Mantle cell lymphoma (MCL) (pathologically confirmed, with monoclonal B cells harboring t(11;14) and/or cyclin D1 overexpression);

   2.1.7 MZL \[including nodal or splenic marginal zone B-cell lymphoma and mucosa-associated lymphoid tissue lymphoma\];

   2.2 Relapsed or refractory disease during the screening period:

   2.2.1 Definition of relapsed disease: achievement of complete remission (CR) after first-line standard therapy (which must include rituximab and an anthracycline), with biopsy-confirmed disease relapse within 12 months after initiation of first-line treatment;

   2.2.2 Definition of refractory disease: failure to achieve CR after first-line standard therapy; subjects who are intolerant to first-line therapy are excluded. At least one of the following criteria must be met:

   2.2.2.1 Best response of progressive disease (PD) after first-line standard therapy;

   2.2.2.2 Best response of stable disease (SD) or PD after at least 4 cycles of first-line standard therapy (e.g., 4 cycles of R-CHOP);

   2.2.2.3 Best response of partial response (PR) after at least 6 cycles of first-line standard therapy, with biopsy-confirmed residual disease, followed by PD within 12 months;

   2.2.2.4 Failure to achieve remission after autologous stem cell transplantation (including SD and PD), or relapse within 12 months after achieving remission (including PR and CR);

   2.2.3 Subjects with transformed DLBCL must have received at least one line of therapy after transformation and have r/r disease after the most recent treatment;

   2.2.4 For subjects with MCL, prior treatment must have included an anthracycline- or bendamustine-containing regimen, anti-CD20 therapy (unless CD20-negative), and a BTK inhibitor;

   2.2.5 For subjects with indolent lymphoma (FL grades 1-3a and MZL), at least second-line prior therapy is required.

3. At least one measurable target lesion, defined as: longest diameter of an intra-nodal lesion \> 1.5 cm; or longest diameter of an extra-nodal lesion \> 1.0 cm (according to the 2014 Lugano Classification response criteria).
4. CD19-positive tumor tissue confirmed by histopathology. A prior CD19 pathology diagnosis may be accepted if confirmed by the investigator. Subjects previously treated with anti-CD19 therapy must undergo tumor biopsy to confirm current CD19-positive expression.
5. Any toxicities from prior therapies must be stable and recovered to Grade ≤ 1 (except for hematologic toxicities and clinically insignificant toxicities such as alopecia).
6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
7. Organ function must meet the following criteria:

   7.1 Hematology: (No G-CSF permitted within 1 week prior to hematology testing, and no pegylated G-CSF within 2 weeks prior to testing): Absolute neutrophil count (ANC) ≥ 1.0 × 10\^9/L; Platelet count (PLT) ≥ 50 × 10\^9/L; Hemoglobin ≥ 60 g/L (This criterion does not apply to bone marrow suppression caused by lymphoma involvement of the bone marrow);

   7.2 Peripheral blood lymphocyte subsets: CD3+ T-lymphocyte count ≥ 100/μL;

   7.3 Coagulation function: International normalized ratio (INR) ≤ 1.5 × ULN; Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN;

   7.4 Hepatic function: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN (or ≤ 5 × ULN in the presence of liver metastases); Total bilirubin ≤ 1.5 × ULN;

   7.5 Renal function: Serum creatinine ≤ 1.5 × ULN, or Creatinine clearance (calculated by the Cockcroft-Gault formula) ≥ 60 mL/min;

   7.6 Cardiac function: Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiography (ECHO); No pericardial effusion; No clinically significant abnormalities on 12-lead electrocardiogram (ECG);

   7.7 Pulmonary function: Oxygen saturation ≥ 92% on room air without supplemental oxygen; No clinically significant pleural effusion;

8. Subjects who are fertile, and/or whose partners are of childbearing potential, must agree to use effective contraception throughout the treatment period and for 24 months after completion of treatment, and must not donate ova or sperm for assisted reproduction during this period. Women of childbearing potential (women who have undergone sterilization or have been postmenopausal for ≥ 12 months are not considered to be of childbearing potential) must have a negative urine or serum pregnancy test during screening.
9. Willing to comply with all study procedures, voluntarily participate in the study, and sign the informed consent form.

Exclusion Criteria:

1. Estimated life expectancy \< 3 months.
2. History of or concurrent active malignancy. Exceptions include curatively treated carcinoma in situ of the cervix, noninvasive basal cell or squamous cell skin cancer, locally confined prostate cancer after definitive treatment, or ductal carcinoma in situ after curative surgery, provided there has been no recurrence for at least 3 years;
3. Prior allogeneic stem cell transplantation, or autologous stem cell transplantation within 3 months prior to planned infusion of BEX101 injection.
4. History of central nervous system (CNS) disease or presence of clinically significant CNS dysfunction, such as cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, epilepsy, aphasia, or other similar conditions.
5. Myocardial infarction, cardiac angioplasty or stent implantation, unstable angina, or other clinically significant cardiac disease within 12 months prior to screening.
6. Lymphoma involvement of the atrium or ventricle.
7. Presence of CNS metastases or symptoms suggestive of CNS metastases.
8. Ongoing or anticipated tumor-related emergency requiring treatment within 6 weeks after signing the informed consent form, such as mass effect from tumor bulk or tumor lysis syndrome.
9. Prior antitumor therapy for which the washout period has not exceeded 5 half-lives before the planned infusion of BEX101 injection.
10. Use of any of the following drugs or treatments within the specified time periods.

10.1 Radiotherapy within 8 weeks prior to administration of the investigational product (except prophylactic treatment for CNS involvement).

10.2 Alemtuzumab within 6 months prior to administration of the investigational product, or fludarabine or bendamustine within 3 months prior to administration.

10.3 Other cytotoxic drug therapy within 2 weeks prior to administration of the investigational product.

10.4 Corticosteroids or immunosuppressive therapy within 1 week prior to administration of the investigational product.

10.5 Monoclonal antibody therapy within 3 weeks prior to administration of the investigational product. 11. Uncontrolled active bacterial, fungal, or viral infection, or any other infection that, in the investigator's judgment, makes the subject unsuitable for study participation. 12. Positive for HIV antibody, positive for Treponema pallidum antibody, positive for hepatitis B surface antigen (HBsAg), or positive for hepatitis B core antibody (HBcAb) with detectable peripheral blood HBV DNA, or positive for hepatitis C virus (HCV) antibody with detectable HCV RNA; exceptions may be made for infections considered preventable or controllable with medication in the investigator's judgment. 13. Known active autoimmune disease requiring systemic treatment. 14. Known severe hypersensitivity to any study medication or any of its components. 15. Pregnant or breastfeeding women.
16. Receipt of a live vaccine within 6 weeks prior to enrollment. 17. Participation in another interventional clinical study within 3 months prior to signing the informed consent form, receipt of active investigational drug treatment, or intention to participate in another clinical trial or receive treatment for autoimmune disease outside the protocol during the study period. 18. Patients with psychiatric disorders such as depression or suicidal ideation/tendency. 19. Any other medical condition that may affect the safety or efficacy evaluation of the investigational product. 20. Any other factor that, in the investigator's judgment, renders the subject unsuitable for enrollment or may interfere with the subject's participation in or completion of the study.