This is a multicenter, open Phase Ib clinical study to evaluate the safety,efficacy and pharmacokinetics of BEBT-908 combined with Rituximab (R) or combined with Rituximab-Gemcitabine-Oxaliplatin (R-GemOx) or combined with Rituximab-Ifosfamide-Carboplatin-Etoposide (R-ICE) in the treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL).

This study sets up three cohorts, including BEBT-908 combined with R, BEBT-908 combined with R-ICE, and BEBT-908 combined with R-GemOx. The researchers decide whether to terminate the cohort study according to the safety and tolerability results of each cohort during the first cycle of medication. If the participants in the above three cohorts are unable to receive the treatment during the first cycle of medication, two alternative cohort studies will be conducted. Namely, BEBT-908 monotherapy (alternative cohort 1), adjustment of BEBT-908 combined with GemOx administration regimen (alternative cohort 2).

The study process for each participant includes a screening period, a treatment period, and a post-treatment follow-up period. During treatment, participants are evaluated for tumors every 6 weeks, follow up after termination of treatment with efficacy follow-up every 6 weeks for those without disease progression and survival follow-up every 3 months until disease progression (PD), death, emergence of intolerable toxicity, or withdrawal of informed consent (whichever occurred first).

Inclusion Criteria:

1. The subject is willing to sign the informed consent form (ICF) after comprehensive understanding;
2. Age ≥18 years and ≤75 years, both male and female;
3. The pathology was confirmed as diffuse large B-cell lymphoma according to the 2016 World Health Organization classification definition;
4. Evaluation by Positron Emission Computed Tomography (PET-CT) or Computed Tomography (CT) or Magnetic resonance imaging (MRI) using Lugano 2014 standard, with measurable lesion injection;
5. Must have recurrent or refractory diffuse large B-cell lymphoma after at least 1 systemic therapy, and at least 1 systemic therapy included CD20 antibody;
6. Eastern Cooperative Oncology Group (ECOG) scores 0-2 points;
7. Life expectancy >12 weeks;
8. The level of organ function must meet the following requirements:

Peripheral blood:

1. Absolute neutrophil count (ANC) ≥1000/μL;
2. Hemoglobin (HGB) ≥8g/dL;
3. Platelet count (PLT) ≥100,000/μL;

Liver function:

1. Serum total bilirubin ≤1.5×ULN (for patients with Gilbert syndrome, total bilirubin <3.0×ULN and Direct bilirubin within normal range);
2. Serum creatinine <1.5×ULN;
3. ALT, AST or ALP≤2.5×ULN (≤5×ULN when liver involvement occurs).

Exclusion Criteria:

1. Known severe allergy to the investigational drug or any of its excipients;

2. Due to the possibility of genotoxicity, mutagenicity and teratogenicity of the investigational drug, the following subjects should be excluded:

   1. Men and women who have not had sperm or egg preservation in vitro before the trial and plan to have another child within 5 years unless subsequent studies confirm reproductive safety;
   2. Pregnant or lactating women;

3. Primary central nervous system lymphoma or lymphoma invading the central nervous system;

4. Previous chronic lymphoma transformation (such as Richter syndrome, prelymphocytic leukemia, etc.);

5. There are other active malignant tumors requiring treatment that may interfere with the study;

6. Pre-trial treatment:

   1. Received any persistent or intermittent PI3K inhibitor and HDAC inhibitor prior to enrollment or received other small-molecule targeted drug therapy within 2 weeks;
   2. Received BEBT-908 (not allowed to be in all cohorts) or R-ICE (not allowed to be in cohorts with BEBT-908+R-ICE) or R-GemOx (not allowed to be in cohorts with BEBT-908+R-GemOx) prior to enrollment;
   3. Autologous hematopoietic stem cell transplantation within 3 months before enrollment;
   4. Received radiotherapy that affected the evaluation of the efficacy of the study or local supportive radiotherapy that affected the bone marrow function of the subjects within 3 months before enrollment;
   5. Received myelosuppressive chemotherapy or biotherapy within 3 weeks prior to enrollment;
   6. Used Chinese medicines and proprietary Chinese medicines with anti-tumor effects within 2 weeks before enrollment;
   7. Undergone major surgery other than tumor biopsy within 4 weeks prior to enrollment, or the side effects of surgery had not stabilized;
   8. Any hematopoietic colony-stimulating factor (e.g., granulocyte colony-stimulating factor G-CSF, granulocyte macrophage colony-stimulating factor GM-CSF) or thrombopoietin TPO were treated within 2 weeks prior to enrollment；
   9. Received prednisone >10mg daily (or another equivalent dose of glucocorticoid) within 7 days prior to enrollment;
   10. Received chimeric antigen receptor T cell immunotherapy (CAR-T therapy) within 3 months before enrollment;

7. Persistent grade 2 or higher [Common Terminology Criteria for Adverse Events V5.0 standard (CTCAE V5.0 standard)] toxicity after previous treatment (chemotherapy or biotherapy), not stable at enrollment (except alopecia);

8. Active clinical severe infection of grade 2 or above (CTCAE V5.0 standard);

9. Complicated diseases:

   1. diabetes mellitus with poor glycemic control (random glycemic value ≥11.1mmol/L after hypoglycemic treatment, or glycosylated hemoglobin（HbA1c）≥ 8.5%);
   2. severe lung disease (CTCAE V5.0 grade III-IV);
   3. Serious heart disease;
   4. have significant kidney or liver dysfunction;
   5. Poorly controlled active diseases such as hepatitis B or C;
   6. Known human immunodeficiency virus (HIV) positive;
   7. A history of mental illness, family history of mental illness, or mood disorder, as judged by the investigator or psychologist, and the researcher judged that they were not suitable for inclusion;
   8. Combination of anticoagulation and antiplatelet therapy is required during the study period;
   9. uncontrolled hypertension (systolic blood pressure ≥180mmHg and/or diastolic blood pressure ≥110mmHg);
   10. Serious physical disease combined with the risk of major bleeding or a history of major bleeding;

10. Combined with use of drugs that cause QT interval prolongation or torsional ventricular tachycardia;

11. Receiving cytochrome P450 (CYP) 3A4 isozyme suppressant or strongly induced drug therapy during the first 4 weeks of enrollment；

12. Participated in other clinical trials and used investigational drugs within 4 weeks before enrollment;

13. Any condition that the investigator determines to be unstable or likely to compromise the subject's safety and compliance with the study;

14. Subjects deemed unsuitable for treatment with this protocol by the investigator.