Orelabrutinib Combined With Pola-R-CHP as First-Line Treatment for Patients With Intermediate- to High-Risk DLBCL

This study is designed to evaluate the efficacy and safety of orelabrutinib in combination with polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) as first-line treatment for patients with intermediate- to high-risk Diffuse large B-cell lymphoma (DLBCL).

Participants will receive orelabrutinib 150 mg orally once daily on Days 1-21 of each 21-day cycle. Polatuzumab vedotin will be administered intravenously at 1.8 mg/kg once every 21 days in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for 6 cycles. During Cycles 7 and 8, participants will receive rituximab in combination with orelabrutinib. Thereafter, orelabrutinib maintenance therapy will be continued for up to 1 year.

• Orelabrutinib Combined with Pola-R-CHP Regimen (Drug), also known as Orelabrutinib in combination with polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP): Participants will receive orelabrutinib 150 mg orally once daily on Days 1-21 of each 21-day cycle. Polatuzumab vedotin will be administered intravenously at 1.8 mg/kg once every 21 days in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for 6 cycles. During Cycles 7 and 8, participants will receive rituximab in combination with orelabrutinib. Thereafter, orelabrutinib maintenance therapy will be continued for up to 1 year.

Primary outcomes

• Complete Response Rate (CRR) [up to 12 months]: The proportion of patients who achieve Complete Response.
• Objective Response Rate (ORR): [up to 12 months]: The proportion of patients who achieve either a complete response (CR) or a partial response (PR, partial reduction of tumor lesions).
• Progression-Free Survival (PFS) [up to 24 months]: The length of time during which a patient's disease does not progress (i.e., no new tumor growth or spread of existing tumors).
• Overall Survival (OS) [up to 24 months]: The length of time from the start of treatment until a patient's death from any cause.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Aged ≥ 18 years;
2. Pathologically confirmed diffuse large B-cell lymphoma (DLBCL) by tumor tissue, with at least one measurable lesion, including DLBCL, not otherwise specified (GCB and non-GCB subtypes), DLBCL with MYC and BCL-2 rearrangements, and high-grade B-cell lymphoma;
3. No prior receipt of other anti-tumor treatments;
4. ECOG performance status 0-2;
5. IPI score 2-5, and patients with stage III-IV disease;
6. Life expectancy ≥ 6 months;
7. Voluntarily sign a written informed consent form.

Exclusion Criteria:

1. Lymphoma involving the central nervous system or leptomeningeal metastasis;
2. Transformed lymphoma, i.e., transformed from other types of lymphoma, such as follicular lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia, or small B-cell lymphoma;
3. Primary mediastinal large B-cell lymphoma;
4. Burkitt lymphoma;
5. Left ventricular ejection fraction < 50%;
6. Laboratory test values at screening: (unless caused by lymphoma);

   1. Neutrophils < 1.5×10⁹/L;
   2. Platelets < 75×10⁹/L;
   3. ALT or AST higher than 2 times the upper limit of normal, AKP and bilirubin higher than 1.5 times the upper limit of normal;
   4. Creatinine level higher than 1.5 times the upper limit of normal;
7. Patients with psychiatric disorders or other patients who are known or suspected to be unable to fully comply with the study protocol;
8. Pregnant or lactating women;
9. Known infection with human immunodeficiency virus (HIV), or active hepatitis B or C virus infection (positive result by polymerase chain reaction \[PCR\]). If a patient has a positive HBsAg test result, HBV DNA testing is required. If HBV DNA < 10³ IU/ml, the patient can be enrolled. If the HBsAg test result is negative, but the HBcAb test is positive (regardless of HBsAb status), HBV DNA testing is also required. If HBV DNA < 10³ IU/ml, the patient can be enrolled. If a patient is HCV antibody positive, HCV RNA is detected by PCR technology, and a positive result meets the exclusion criterion;
10. Need for continuous treatment with strong or moderate CYP3A inhibitors or CYP3A inducers;
11. nability to swallow capsules or presence of diseases that significantly affect gastrointestinal function, such as malabsorption syndrome, bariatric surgery, inflammatory bowel disease, or partial or complete intestinal obstruction;
12. Other concurrent and uncontrolled medical conditions that the investigator deems will affect the patient's participation in the study.

• Bing Xu, PhD，MD, Principal investigator, The First Affiliated Hospital of Xiamen University