Serplulimab, Chidamide, and Rituximab Followed by Sequential R-CHOP for Newly Diagnosed Elderly MYC/BCL2 Double-Expressor DLBCL

A Phase II Study of Serplulimab, Chidamide, and Rituximab Followed by R-CHOP in Newly Diagnosed Elderly Patients With MYC/BCL2 Double-Expressor Diffuse Large B-Cell Lymphoma

This study is a phase II clinical trial and is divided into three stages.

Stage 1: Chemotherapy-free phase. All subjects will receive "Serplulimab, Chidamide, and Rituximab (SCR) therapy". After 2 treatment cycles, efficacy will be evaluated. Subjects who achieve CR or CMR will continue to receive 2 additional cycles of SCR therapy. Patients who do not achieve CR or CMR will proceed to Stage 2 treatment. The SCR regimen consists of rituximab 375mg/m² IV on day 1, serplulimab 300mg IV on day 2, and chidamide 30mg PO twice weekly (on days 1, 4, 8, 11, 14, and 18), repeated every 21 days.

Stage 2: Chemotherapy Phase. Subjects who achieved CR or CMR in Stage 1 will receive 4 cycles of R-CHOP therapy, while those who did not achieve CR or CMR will receive 6 cycles of R-CHOP therapy. Patients at high risk for central nervous system (CNS) involvement will receive consensus-recommended CNS prophylactic therapy (e.g., high-dose methotrexate). The R-CHOP regimen is administered at the following dosages: rituximab 375mg/m², cyclophosphamide 750mg/m², doxorubicin 50mg/m², all administered intravenously on day 1; vincristine 1.4mg/m² (max 2mg) intravenously on day 1; and prednisone 100mg orally on days 1-5. The treatment cycle is repeated every 21 days. For patients over 75 years of age or those considered frail, the R-miniCHOP regimen may be utilized.

Stage 3: Maintenance Therapy. Subjects who achieve CR/CMR or PR/PMR in Stage 2 will proceed to the maintenance phase, receiving serplulimab in combination with chidamide for 6 months. Subjects who do not achieve CR/CMR or PR/PMR in Stage 2 will be withdrawn from the study. During the maintenance phase, the regimen consists of serplulimab 300mg administered intravenously on day 1 and chidamide 30mg administered orally twice per week (specifically on days 1, 4, 8, 11, 14, and 18) of a 30-day cycle.

Inclusion Criteria:

1. Voluntarily participate in the clinical study; fully understand and are informed about the study and sign the Informed Consent Form (ICF); willing and able to comply with and complete all trial procedures.

2. Age ≥ 60 years and ≤ 80 years at the time of signing the ICF.

3. Treatment-naïve, having received no prior anti-lymphoma therapy.

4. Confirmed diagnosis of Diffuse Large B-Cell Lymphoma (DLBCL) by central histopathology, meeting the following criteria:

   Concurrent positive expression of MYC and BCL2 proteins (IHC WHO standards: MYC ≥40%, BCL2 ≥50%).

   Not a "double-hit" or "triple-hit" lymphoma: FISH testing must not show the presence of "MYC and BCL2 rearrangements" or "MYC and BCL6 rearrangements" or "MYC and BCL2 and BCL6 rearrangements".

5. Lugano clinical stage II-IV, or stage I with bulky disease (mass diameter >7.5 cm).

6. International Prognostic Index (IPI) score of 2-5.

7. Availability of archival or freshly obtained tumor tissue samples from core needle biopsy or excision (10-15 unstained, freshly frozen, formalin-fixed paraffin-embedded [FFPE] slides).

8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

9. Life expectancy greater than 12 months.

10. Must have at least one evaluable or measurable lesion according to the LYRIC 2016 criteria.Evaluable lesion: 18FDG/PET scan showing focally increased nodal or extranodal uptake (higher than liver) with PET and/or CT features consistent with lymphoma. Measurable lesion: Nodal lesion with long axis >15 mm or extranodal lesion with long axis >10 mm (if the only measurable lesion was previously irradiated, there must be evidence of post-radiation progression), accompanied by increased 18FDG uptake.Cases with no measurable lesions and diffuse hepatic 18FDG uptake higher than liver are excluded.

11. Adequate organ and bone marrow function, without severe hematological abnormalities or significant cardiac, pulmonary, hepatic, renal, thyroid dysfunction, or immunodeficiency (without transfusion, granulocyte colony-stimulating factor, or other relevant medical support within 14 days prior to study drug administration):

    1. Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L (≥1.0 × 10⁹/L for patients with bone marrow involvement).
    2. Platelets ≥75 × 10⁹/L (≥50 × 10⁹/L for patients with bone marrow involvement).
    3. Hemoglobin ≥9 g/dL.
    4. Serum creatinine ≤1.5 × Upper Limit of Normal (ULN), OR creatinine clearance ≥40 mL/min (calculated using the Cockcroft-Gault formula).
    5. Serum total bilirubin ≤1.5 × ULN.
    6. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤2.5 × ULN or ≤5 × ULN (in cases of hepatic involvement by lymphoma).
    7. Coagulation: International Normalized Ratio (INR) ≤1.5 × ULN; Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT) ≤1.5 × ULN (unless the subject is receiving anticoagulant therapy and PT/APTT at screening is within the therapeutic range for the intended use of anticoagulants).
    8. Thyroid-Stimulating Hormone (TSH), Free Thyroxine (FT4), or Free Triiodothyronine (FT3) within normal range ±10%.

12. No evidence of dyspnea at rest, and a resting pulse oximetry reading >92%.

Exclusion Criteria:

1. Primary central nervous system (CNS) lymphoma or secondary CNS involvement.

2. Primary mediastinal (thymic) large B-cell lymphoma, primary effusion DLBCL, unclassifiable B-cell lymphoma with features intermediate between DLBCL and classical Hodgkin lymphoma (grey zone lymphoma), primary cutaneous DLBCL, leg type, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, HHV8-positive DLBCL.

3. Transformed lymphoma, i.e., transformed from other types of lymphoma such as follicular lymphoma, marginal zone B-cell lymphoma, or chronic lymphocytic leukemia/small lymphocytic lymphoma.

4. History of severe hypersensitivity or anaphylactic reactions to humanized or murine monoclonal antibodies.

5. Presence of an active autoimmune disease that has required systemic treatment within the past two years. Replacement therapy (e.g., thyroxine for hypothyroidism, insulin for type I diabetes mellitus, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. Patients with autoimmune diseases that did not require systemic treatment in the past two years may be enrolled.

6. Systemic corticosteroid therapy (>10 mg/day prednisone or equivalent) or other immunosuppressive therapy within 14 days prior to the start of study treatment. The use of topical, ocular, intra-articular, intranasal, or inhaled corticosteroids (with minimal systemic absorption) is permitted. Short-term (≤7 days) prophylactic use of corticosteroids (e.g., for contrast allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted. An exception may be made for patients requiring corticosteroids for symptom control due to high tumor burden (prednisone up to 100mg/day or equivalent, for a maximum of 7 days is permitted).

7. Diagnosis of another malignancy within the past 5 years, except for malignancies treated with curative intent, including basal cell carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ of the breast, or carcinoma in situ of the cervix.

8. Prior systemic anti-tumor therapy within 28 days before the start of study treatment, including chemotherapy, immunotherapy, or biologic therapy (e.g., cancer vaccines, cytokines, or growth factors targeting cancer control).

9. Major surgery within 28 days prior to the start of study treatment, or radiotherapy within 90 days prior.

10. Treatment with Chinese herbal medicines or proprietary Chinese medicines with anti-cancer indications within 7 days prior to the start of study treatment.

11. Administration of a live vaccine within 28 days prior to the start of study treatment, with the exception of inactivated influenza vaccines.

12. Known history of infection with Human Immunodeficiency Virus (HIV) and/or Acquired Immunodeficiency Syndrome (AIDS).

13. Patients with active chronic hepatitis B or active hepatitis C.

    * Patients who are positive for Hepatitis B surface antigen (HBsAg) or Hepatitis C virus (HCV) antibody during screening are eligible only if subsequent testing confirms: HBV DNA titer ≤ 2500 copies/mL or 1000 IU/mL, AND/OR HCV RNA below the lower limit of detection of the assay.

    * This is to exclude patients with active hepatitis B or C infection requiring therapy. Asymptomatic carriers with controlled HBV (DNA titer as above) or cured hepatitis C are eligible.

14. Any active infection requiring systemic anti-infective therapy within 14 days prior to the start of study treatment.

15. Uncontrolled concurrent illness, including but not limited to: symptomatic congestive heart failure, uncontrolled hypertension, unstable angina, active peptic ulcer disease, or bleeding disorders.

16. History of interstitial lung disease or non-infectious pneumonitis. Patients with a history of drug-induced or radiation-induced non-infectious pneumonitis that is asymptomatic may be enrolled.

17. QTcF interval > 450 msec, unless secondary to bundle branch block.

18. Any underlying medical condition that, in the investigator's judgment, would substantially increase the risk associated with the patient's participation in the study, or confound the interpretation of toxicities.

19. Any other condition that, in the opinion of the investigator, renders the patient unsuitable for participation in the study.