Genetic Subtype-matched Targeted Therapy for the Treatment of Newly Diagnosed DLBCL With TP53 Mutation

A Prospective, Exploratory Clinical Study of Genetic Subtype-matched Precision Targeted Therapy in Newly Diagnosed DLBCL With TP53 Mutation

To evaluate the efficacy and safety of Genetic subtype-matched targeted therapy in the treatment of treatment-naive diffuse large B-cell lymphoma with TP53 mutation.

Study Overview

• Status: Recruiting
• Conditions: Diffuse Large B-Cell Lymphoma (DLBCL)
• Intervention / Treatment: Drug: POLA-R-CHP; Drug: Orelabrutinib

Detailed Description

Using Genetic subtype-matched targeted therapy as first-line treatment for patients with treatment-naive diffuse large B-cell lymphoma (DLBCL) harboring TP53 mutations. The specific Genetic subtype-matched targeted therapy regimen is as follows:

For patients with the MCD/BN2 subtype: Pola-R-CHP + orelabrutinib; For patients with other subtypes: Pola-R-CHP

• Study Type: Interventional
• Enrollment (Estimated): 35
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Changju Qu; Phone Number: 67781865; Email: qcj310@163.com

Study Locations

• China
  • Jiangsu
    • Suzhou, Jiangsu, China, 215006
      • Recruiting
      • the First Affiliated Hospital of Soochow University
      • Contact: Changju Qu; Phone Number: 67781865; Email: qcj310@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients aged 18 years and older, up to 70 years.
2. Participants must be able to understand and willing to sign the written informed consent form.
3. Eastern Cooperative Oncology Group performance status 0 to 3.
4. Life expectancy ≥3 months (as determined by the investigator).
5. Pathologically (histologically or cytologically) confirmed treatment-naive CD20-positive diffuse large B-cell lymphoma.
6. Measurable disease defined by PET-CT as a short-axis diameter of at least ≥1.5 cm.

7. Bone marrow and organ function meeting the following criteria (without blood transfusion, G-CSF, or medication correction within 14 days prior to screening):

   Bone marrow function: Absolute neutrophil count ≥1.5×10⁹/L, platelet count ≥80×10⁹/L, hemoglobin ≥80 g/L.

   Liver function: Total serum bilirubin ≤1.5×ULN (≤3.0×ULN if liver metastases present); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN (≤5.0×ULN if liver metastases present).

   Coagulation function: International normalized ratio (INR) and activated partial thromboplastin time ≤1.5×ULN.

   Renal function: Serum creatinine ≤1.5×ULN or estimated creatinine clearance ≥60 mL/min (for males: Cr (mL/min) = (140 - age) × body weight (kg) / [72 × serum creatinine concentration (mg/dL)]; for females: Cr (mL/min) = (140 - age) × body weight (kg) / [85 × serum creatinine concentration (mg/dL)]).

8. Females of childbearing potential must agree to use highly effective contraceptive methods during the treatment period and for 5 weeks after the last dose of study drug. Sexually active males must agree to use highly effective contraception during the treatment period and for 3 months after the last dose.
9. No difficulty swallowing oral tablets/capsules.
10. Good compliance and willingness to adhere to visit schedules, dosing schedules, laboratory tests, and other examination procedures.

Exclusion Criteria:

1. Patients who have previously received systemic anti-tumor therapy.
2. Patients with central nervous system involvement.
3. Patients who received systemic adrenal corticosteroids for more than 5 days within 14 days prior to study drug administration, or who require daily doses of >10 mg of dexamethasone or equivalent drugs to control central nervous system disease.
4. Active concurrent malignancy requiring active treatment.
5. Uncontrolled or severe cardiovascular disease, including (but not limited to) any of the following: congestive heart failure (NYHA class III or IV); myocardial infarction; unstable angina; or presence of arrhythmia requiring treatment at screening, with left ventricular ejection fraction (LVEF) < 50% within 6 months prior to the first dose; primary cardiomyopathy (e.g., dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, undefined cardiomyopathy); clinically significant history of QTc prolongation, second-degree type II atrioventricular block or third-degree atrioventricular block, or QTc interval (Fridericia's method) > 470 ms (female) or > 480 ms (male); atrial fibrillation; patients with uncontrolled hypertension considered unsuitable for participation in the study.
6. Uncontrolled infection or infection requiring intravenous antibiotic therapy.

7. Chronic hepatitis B carriers with active hepatitis B or hepatitis C infection (hepatitis B: acute hepatitis B, untreated chronic hepatitis B virus infection, HBV-DNA ≥ the detection limit of the respective center; hepatitis C: HCV RNA positive) or syphilis. Note: Inactive hepatitis B surface antigen (HBsAg) carriers, subjects with active HBV infection and sustained HBV suppression (HBV DNA < detection limit of the respective center), and subjects cured of HCV may be enrolled.

   Human immunodeficiency virus (HIV) infection.

8. Clinically significant gastrointestinal abnormalities that may affect drug intake, transport, or absorption (such as active gastrointestinal inflammation, chronic diarrhea, intestinal obstruction, etc.), or patients with total gastrectomy, gastric banding surgery, or tumor involvement of the gastrointestinal tract.
9. Patients with a history of bleeding disorders, or patients requiring long-term oral anticoagulation due to comorbidities.
10. Female subjects who are currently pregnant or breastfeeding.
11. Allergy to the study drug or excipients.
12. Patients with active psychiatric disorders, alcohol dependence, drug dependence, or substance abuse.
13. Presence of any life-threatening disease, medical condition, or organ system dysfunction that, in the investigator's opinion, may affect patient safety or compliance with study procedures.
14. Other conditions that, in the investigator's opinion, make the patient unsuitable for participation in this clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Pola-R-CHP + orelabrutinib or Pola-R-CHP; Using Genetic subtype-matched targeted therapy as first-line treatment for patients with treatment-naive diffuse large B-cell lymphoma (DLBCL) harboring TP53 mutations. The specific Genetic subtype-matched targeted therapy regimen is as follows: Induction treatment period (6 cycles, 21 days/cycle): For patients with the MCD/BN2 subtype: Pola-R-CHP + orelabrutinib; For patients with other subtypes: Pola-R-CHP Consolidation treatment period (2 cycles, 21 days/cycle)： For patients with the MCD/BN2 subtype: R + orelabrutinib; For patients with other subtypes: R

Drug: POLA-R-CHP; Induction treatment period (6 cycles, 21 days/cycle): Polatuzumab vedotin: 1.8 mg/kg, intravenous drip, Day 1 of each cycle Rituximab: 375 mg/m2, intravenous drip, Day 1 of each cycle CHP/CDP Regimen Cyclophosphamide: 750 mg/m² , intravenous drip, Day 2 of each cycle Doxorubicin: 50 mg/m² , intravenous drip, Day 2 of each cycle or Doxorubicin Hydrochloride Liposome: 25 mg/m² , intravenous drip, Day 2 of each cycle Prednisone: 100 mg, Days 2-6 of each cycle. Consolidation treatment period (2 cycles, 21 days/cycle): Rituximab: 375 mg/m2, intravenous drip, Day 1 of each cycle; Drug: Orelabrutinib; Induction treatment period (6 cycles, 21 days/cycle)+Consolidation treatment period (2 cycles, 21 days/cycle). Orelabrutinib: 150mg orally per day from Days 1 to 21 of cycles 2-6 (MCD/BN2)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
2-year progression-free survival(PFS)	PFS will be assessed from the start of the treament to date of progression, relapse, death or end of follow-up.	From date of signing the informed consent until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete response rate(CRR)	The rate of patients who achieved CR after 6 cycles	At the end of 6 cycles (each cycle is 21 days)
2-year overall survival(OS)	OS will be assessed from the start the treatment to date of death or end of follow-up.	From date of signing the informed consent until the date of death from any cause, whichever came first, assessed up to 2 years

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital of Soochow University

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: March 24, 2026
• First Submitted That Met QC Criteria: March 24, 2026
• First Posted (Actual): March 30, 2026

Study Record Updates

• Last Update Posted (Actual): March 30, 2026
• Last Update Submitted That Met QC Criteria: March 24, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Diffuse Large B-Cell Lymphoma; orelabrutinib; TP53 mutation; Polatuzumab vedotin
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma; Hemic and Lymphatic Diseases; Lymphoma, Large B-Cell, Diffuse; orelabrutinib
• Other Study ID Numbers: 2026090

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No