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

Official title

A Prospective, Phase II, Multicenter Clinical Study of Pirtobrutinib Combined With Sonrotoclax Regimen in the Treatment of B-Cell Lymphoma

Overview

This prospective, open-label, Phase II clinical trial evaluates the efficacy and safety of pirtobrutinib combined with sotoclax across three distinct B-cell lymphoma cohorts: histologically transformed diffuse large B-cell lymphoma (DLBCL), relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and relapsed/refractory marginal zone lymphoma (MZL). Dosing regimen ：pirtobrutinib 200 mg orally once daily plus sotoclax with a 4-week dose escalation schedule (1, 2, 5, 10, 20, 40, 80, 160 mg/day, then 320 mg/day on days 1-28, starting Cycle 2) administered orally. Cohorts 1 and 2 additionally incorporate obinutuzumab 1000 mg intravenously on Cycle 1 days 1, 8, and 15, followed by days 1 of Cycles 2 through 6, with a maximum of six cycles. Each treatment cycle spans 28 days. For Cohort 1 (RT DLBCL), the primary objective centers on early response assessment following three cycles of the PSO regimen (pirtobrutinib-sotoclax-obinutuzumab), with PET/CT evaluation serving as the critical decision point. Patients demonstrating progressive disease or stable disease discontinue study treatment, while those achieving complete or partial response may proceed to investigator-selected bridging therapies including bispecific antibodies, CAR-T cell therapy, or hematopoietic stem cell transplantation, or alternatively continue PSO combination therapy. Obinutuzumab is capped at six cycles, whereas pirtobrutinib and sotoclax may continue for up to 25 cycles. Comprehensive biomarker strategies include ctDNA analysis from peripheral blood at baseline and after Cycle 1 (following full-dose sotoclax exposure), with serial assessments at Cycles 3, 7, 14, and every six cycles during Year 2 for patients continuing PSO beyond Cycle 3. Patients with measurable baseline tumor cells in peripheral blood or bone marrow undergo flow cytometry-based MRD detection at 10-⁴ sensitivity at corresponding timepoints. T-cell subset and functional analyses are performed at baseline, Cycle 3, and every three cycles thereafter to characterize immune dynamics during treatment. Cohort 2 (relapsed/refractory CLL/SLL) follows a continuous treatment paradigm without an early stopping rule, with efficacy assessment after fourteen cycles. Patients achieving complete remission with MRD negativity at 10-⁴ may elect treatment discontinuation. Sotoclax is administered for a maximum of twenty-four cycles, with pirtobrutinib maintenance for patients failing to achieve MRD-negative complete remission. The biomarker program incorporates both flow cytometry MRD at 10-⁴ and next-generation sequencing MRD at 10-⁶ sensitivity, providing unprecedented depth of residual disease characterization. Sampling occurs at baseline, Cycle 1, Cycle 3, Cycle 7, Cycle 14, and every six cycles in Year 2. Cohort 3 (relapsed/refractory MZL) mirrors the CLL/SLL treatment structure but omits obinutuzumab, testing the doublet of pirtobrutinib plus sotoclax. The fourteen-cycle efficacy assessment and MRD-guided stopping rule apply identically, with sotoclax limited to twenty-four cycles and pirtobrutinib maintenance for non-responders. ctDNA surveillance occurs at baseline, Cycle 3, Cycle 7, Cycle 14, and every six cycles in Year 2, complemented by serial T-cell immunophenotyping.

Detailed description

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.

Interventions

• Drug Pirtobrutinib, Sotoclax+/- Obinutuzumab (PSO) Combination for B cell lymphoma
  Pirtobrutinib, Sotoclax+/- Obinutuzumab (PSO) Combination for B cell lymphoma

Primary outcome measures

• Objective Response Rate (ORR) after 14 cycles of induction therapy [Time frame: week 56，at the end of 14 cycle of PSO/PS regimen（each cycle is 28 days）]

Secondary outcome measures (4)

• Complete Response Rate (CRR) after 14 cycles of induction therapy [Time frame: week 56，at the end of 14 cycle of PSO/PS regimen（each cycle is 28 days）]
• Overall Survival (OS) [Time frame: up to 3 years]
• Event-Free Survival (EFS) [Time frame: up to 3 years]
• Number of participants with treatment-related adverse events (TRAEs) as assessed by CTCAE v5.0 [Time frame: up to 3 years]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Jiangsu Province Hospital The First Affiliated Hospital with Nanjing Medical University — Nanjing

Identifiers

NCT: NCT07744750 · 2026CELH027-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗