Background and Significance: Previous clinical results showed that the benefit of available BTK inhibitors may be limited to non-germinal center B-cell (GCB) subtype of Diffuse large B-cell lymphoma (DLBCL). Birelentinib is a novel LYN/BTK dual inhibitor with complete BBB penetration. As a single agent, birelentinib has demonstrated significant anti-tumor activity and a favorable safety profile in r/r DLBCL (48.4% ORR and 35.5% CRR, EHA 2025, Poster PF962). More importantly, similar responses have been observed in both GCB and non-GCB subtypes. Preclinical data showed strong synergistic effects between Birelentinib and other approved agents. The ongoing TAI-SHAN12 study (NCT07059650) is a phase 2 study further exploring birelentinib based combination regimens.

Study Design and Methods: This phase II multicenter study aims to evaluate the efficacy and safety of Birelentinib in combination with standard therapies for DLBCL. The study consists of three arms: Arm 1: Birelentinib + R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) for 6 cycles. Arm 2: Birelentinib + R-GemOx (rituximab, gemcitabine, oxaliplatin) for 8 cycles. Arm 3: Birelentinib + BR (rituximab, bendamustine) for 6 cycles. Birelentinib will be given on days 1-21 of each 21-day cycle across all arms. Patients achieving complete response (CR) or partial response (PR) following the combination induction will continue with Birelentinib monotherapy for up to 2 years.

Key eligibility criteria include adult patients aged ≥18 years with histologically confirmed DLBCL, ECOG performance status 0–2, adequate bone marrow reserve, and organ function. Arm 1 enrolls treatment-naïve patients, Arms 2 and 3 enroll r/r DLBCL patients with prior R-CHOP-like regimen, ineligible or unwilling for stem cell transplantation. Key exclusion criteria include transformations of indolent B-cell lymphomas, primary mediastinal lymphoma, central nervous system involvement, or MYC and BCL2 rearrangements.

The study is divided into two parts: Part A (dose escalation) employs a Bayesian Optimal Interval (BOIN) design, beginning with a Birelentinib dose of 50 mg QD, the next planned escalation dose is 75 mg QD. Each dose level plans to enrol 3- 10 patients. The primary objective is to determine the safety and recommended Phase 2 combination dose (RP2CD). Part B (expansion) will enrol 10-30 patients per combination arm at the RP2CD. The primary objective is to assess the efficacy by investigator evaluated objective response rate (ORR) according to Lugano 2014 criteria. Other key efficacy endpoints include complete response rate (CRR), time to response (TTR), and duration of response (DoR). Pharmacokinetic analyses will be conducted as secondary objectives in both parts of the study.

Patient enrollment for this study commenced in July 2025 and is currently ongoing.

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2025
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