Pirtobrutinib+Sonrotoclax（PS) Regimen in the Treatment of B-Cell Lymphoma

This is a prospective, open-label, Phase II clinical study aimed at investigating the efficacy and safety of pirtobrutinib combined with sotoclax in the treatment of B-cell lymphoma.

Cohort 1: Histologically transformed DLBCL Pirtobrutinib: 200 mg, po, qd Sotoclax: Dose escalation over 4 weeks: 1, 2, 5, 10, 20, 40, 80, 160 mg/day, followed by 320 mg/day, d1-28, po, starting from Cycle 2 Obinutuzumab: 1000 mg, iv, C1: d1, d8, d15; C2-C6: d1 Each cycle consists of 28 days. Patients receive treatment with pirtobrutinib combined with sotoclax and obinutuzumab (PSO regimen) for 3 cycles, followed by PET/CT evaluation. Patients with PD/SD will be discontinued from the study. Patients with CR/PR will, at the investigator's discretion, proceed to bridging therapy with bispecific antibodies, CAR-T, or HSCT, or continue treatment with pirtobrutinib combined with sotoclax and obinutuzumab. Efficacy assessments will be conducted every 3 cycles. Obinutuzumab will be administered for a maximum of 6 cycles; pirtobrutinib and sotoclax combination therapy will be administered for a maximum of 25 cycles.

Peripheral blood will be collected at baseline and after 1 cycle of treatment (following full-dose sotoclax in C1) for ctDNA detection. For patients who continue PSO combination therapy after 3 cycles, peripheral blood plasma will be collected after 3 cycles, 7 cycles, 14 cycles, and every 6 cycles in Year 2 for ctDNA detection.

For patients with measurable tumor cells in peripheral blood and/or bone marrow at baseline, minimal residual disease (MRD) will be assessed by flow cytometry (10-⁴ sensitivity) at baseline, after 1 cycle, after 3 cycles, after 7 cycles, after 14 cycles, and every 6 cycles in Year 2.

Peripheral blood will be collected at baseline, after 3 cycles, and every 3 cycles thereafter for T-cell subset and functional analysis.

Cohort 2: Relapsed/Refractory CLL/SLL Pirtobrutinib: 200 mg, po, qd Sotoclax: Dose escalation over 4 weeks: 1, 2, 5, 10, 20, 40, 80, 160 mg/day, followed by 320 mg/day, d1-28, po, starting from Cycle 2 Obinutuzumab: 1000 mg, iv, C1: d1, d8, d15; C2-C6: d1 Each cycle consists of 28 days. Patients receive treatment with pirtobrutinib combined with sotoclax and obinutuzumab. Efficacy assessment will be conducted after 14 cycles. Patients who achieve CR with MRD negativity (10-⁴) may choose to discontinue treatment. Sotoclax will be administered for a maximum of 24 cycles; patients who have not achieved MRD negativity will continue pirtobrutinib maintenance.

For patients with measurable tumor cells in peripheral blood and/or bone marrow at baseline, MRD will be assessed by flow cytometry (10-⁴ sensitivity) and NGS-MRD (10-⁶ sensitivity) at baseline, after 1 cycle, after 3 cycles, after 7 cycles, after 14 cycles, and every 6 cycles in Year 2.

Cohort 3: Relapsed/Refractory MZL Pirtobrutinib: 200 mg, po, qd Sotoclax: Dose escalation over 4 weeks: 1, 2, 5, 10, 20, 40, 80, 160 mg/day, followed by 320 mg/day, d1-28, po, starting from Cycle 2 Each cycle consists of 28 days. Patients receive treatment with pirtobrutinib combined with sotoclax. Efficacy assessment will be conducted after 14 cycles. Patients who achieve CR with MRD negativity (10-⁴) may choose to discontinue treatment. Sotoclax will be administered for a maximum of 24 cycles; patients who have not achieved MRD negativity will continue pirtobrutinib maintenance.

Peripheral blood plasma will be collected at baseline, after 3 cycles, after 7 cycles, after 14 cycles, and every 6 cycles in Year 2 for ctDNA detection.

Peripheral blood will be collected at baseline, after 3 cycles, and every 3 cycles thereafter for T-cell subset and functional analysis.

Inclusion criteria

• Cohort 1: Histologically transformed DLBCL

• Histopathologically confirmed histologically transformed DLBCL, including transformation from indolent lymphomas such as CLL, WM, FL, and MZL.
• Whole-body PET/CT performed within 28 days prior to study enrollment demonstrating at least one measurable lesion in two perpendicular dimensions (longest diameter >15 mm for nodal lesions, or longest diameter >10 mm for extranodal lesions).
• Except patients with Richter transformation, patients transformed from MZL, FL, WM, etc., must have received at least one line of systemic anti-lymphoma therapy either during the indolent phase or after transformation.

Cohort 2: Relapsed/refractory CLL/SLL

• Histopathologically confirmed relapsed/refractory CLL/SLL.
• Disease relapse or refractoriness after at least one line of systemic anti-lymphoma therapy, which may include a BTK inhibitor.

Cohort 3: Relapsed/refractory MZL

1.Histopathologically confirmed relapsed/refractory MZL. 2.Received systemic therapy containing an anti-CD20 monoclonal antibody or a BTK inhibitor.

3.Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2. 4.Age ≥ 18 years. 5.Adequate organ and bone marrow function defined as follows:

• Hematologic function (assessed within 7 days prior to Cycle 1 Day 1 [C1D1]): a. Absolute neutrophil count (ANC) ≥ 0.5 × 10⁹/L. Patients with values below this threshold may be eligible if there is documented bone marrow involvement impairing hematopoiesis. b. Platelet count ≥ 50 × 10⁹/L without transfusion support. Patients with values below this threshold may be eligible if there is documented bone marrow infiltration impairing hematopoiesis. c. If transfusions are administered to treat thrombocytopenia or anemia, the patient must demonstrate a response to transfusion support.
• Coagulation function: Activated partial thromboplastin time (aPTT), prothrombin time (PT), or international normalized ratio (INR) ≤ 1.5 × upper limit of normal (ULN).
• Hepatic function: Serum total bilirubin (TBIL) ≤ 1.5 × ULN; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN.
• Renal function: Serum creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance (CCr) ≥ 30 mL/min.
• Cardiac function: New York Heart Association (NYHA) functional class less than Class III; ejection fraction ≥ 50% on echocardiogram.

6.Estimated survival > 3 months. 7.Able to provide written informed consent and comply with protocol-specified study visits and procedures.

8.Female subjects of childbearing potential, or male subjects whose female partners are of childbearing potential, must utilize effective contraceptive measures throughout the treatment period and for 90 days after the last dose of study treatment.

Exclusion criteria

• DLBCL with central nervous system or leptomeningeal involvement;
• Prior treatment with a non-covalent BTK inhibitor;
• Prior treatment with immune checkpoint inhibitors;
• Contraindication or hypersensitivity to any drug in the combination treatment regimen;
• Concurrent other malignancies requiring treatment or intervention;
• Major surgery within 4 weeks prior to treatment (excluding vascular access catheterization or biopsy);
• Any life-threatening disease, medical condition or organ dysfunction that, in the Investigator's opinion, may compromise patient safety or compliance with study procedures;
• Uncontrolled clinical cardiac signs or diseases, including: i. Heart failure of NYHA Class ≥ II ii. Unstable angina pectoris iii. Myocardial infarction within the past 12 months iv. Clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention;
• Patients with active bleeding;
• Active and uncontrolled systemic bacterial, viral, fungal or parasitic infection (excluding fungal nail infection), or other clinically significant active disease process rendering the patient unsuitable for trial participation as judged by the Investigator.
• Patients with active chronic hepatitis B or active hepatitis C. Patients positive for Hepatitis B surface antigen (HBsAg) and/or Hepatitis B core antibody (HBcAb), or Hepatitis C virus (HCV) antibody at screening must undergo further Hepatitis B virus (HBV) DNA testing (≤2500 copies/mL or ≤500 IU/mL) to rule out active hepatitis B or active hepatitis C requiring treatment before enrollment. Nevertheless, eligible patients with positive HBsAg and/or HBcAb must receive anti-hepatitis B antiviral therapy.
• Patients infected with Human Immunodeficiency Virus (HIV) and/or patients with acquired immunodeficiency syndrome (AIDS);
• Inability to swallow tablets, presence of malabsorption syndrome, or any other gastrointestinal disease or dysfunction that may affect absorption of the study drug;
• Pregnant or lactating women;
• Patients with psychiatric disorders or those unable to provide informed consent;
• Patients deemed unsuitable for participation in this study by the Investigator.