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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
40
Pirtobrutinib, Sotoclax+/- Obinutuzumab (PSO) Combination for B cell lymphoma
Jiangsu Province Hospital The First Affiliated Hospital with Nanjing Medical University
Nanjing, Jiangsu, China
Objective Response Rate (ORR) after 14 cycles of induction therapy
Objective Response Rate (ORR) after 14 cycle induction therapy
Time frame: week 56，at the end of 14 cycle of PSO/PS regimen（each cycle is 28 days）
Complete Response Rate (CRR) after 14 cycles of induction therapy
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
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