Phase 3 Randomized Double‑Blind Trial of Orelabrutinib Combined with Rituximab and Bendamustine versus Rituximab‑Bendamustine in Treatment‑Naïve Mantle Cell Lymphoma

The primary objective is to assess whether the addition of orelabrutinib to rituximab‑bendamustine (BR) improves progression‑free survival compared with BR alone in treatment‑naïve mantle cell lymphoma, a direct indicator of disease control and long‑term clinical benefit.

Secondary objectives include:

• Comparison of the combination versus BR on overall survival to evaluate potential extension of life expectancy.
• Further evaluation of efficacy parameters such as response rates and duration of response.
• Detailed assessment of the safety profile of orelabrutinib when combined with BR.
• Analysis of patient‑reported outcomes related to well‑being and general health status.
• Characterization of the pharmacokinetics of orelabrutinib in the combination regimen.

The trial enrolled 374 participants diagnosed with treatment‑naïve mantle cell lymphoma (MCL). Eligible individuals were either 65 years of age or older, or between 60 and 64 years old and ineligible for or refusing stem‑cell transplantation. All subjects required histopathological confirmation of MCL with Cyclin D1 expression and/or t(11;14) translocation, a modified Ann Arbor stage II–IV disease requiring systemic therapy, at least one measurable lesion (lymph node >1.5 cm or extranodal lesion >1.0 cm), and an Eastern Cooperative Oncology Group performance‑status score of 0–2. Participants had not received any prior systemic therapy for MCL. Both male and female patients were included, encompassing vulnerable populations as defined by the protocol. Selection was based on fulfillment of these inclusion criteria and central laboratory confirmation of diagnosis after randomization.

The study is a randomized, double‑blind, multicenter, placebo‑controlled Phase 3 trial evaluating orelabrutinib in combination with rituximab and bendamustine versus rituximab plus bendamustine alone in subjects with treatment‑naïve mantle cell lymphoma. After a screening visit, eligible participants are randomized 1:1 to receive oral orelabrutinib 150 mg daily plus intravenous rituximab 375 mg/m² and bendamustine 90 mg/m² on days 1‑2 of each 28‑day cycle, or matching placebo with the same rituximab‑bendamustine regimen; the oral study drug and placebo are masked to maintain blinding. Treatment is administered for up to six cycles, followed by a safety follow‑up and an end‑of‑study visit. Study visits are scheduled at screening, baseline/randomization, day 1 of each treatment cycle, end of treatment, and every three months thereafter for disease assessment until progression, death, or study completion. Participant involvement is expected to span approximately 24 months, covering active treatment and follow‑up. Early termination may occur if a participant experiences a treatment‑related grade ≥ 3 adverse event, withdraws consent, or meets protocol‑specified efficacy stopping criteria. Recruitment is planned from July 2026 to March 2031, with all assessments conducted according to the protocol‑defined schedule.

Orelabrutinib is supplied as a 150 mg tablet for oral administration. The investigational regimen requires the tablet to be taken once daily throughout the treatment period, with dosing recorded in the study diary to facilitate compliance monitoring.

Truxima 100 mg concentrate for solution for infusion contains the monoclonal antibody rituximab. It is provided as a solution for infusion and administered intravenously at a dose of 375 mg/m². Infusions are performed on the designated day(s) of each treatment cycle in accordance with the protocol, and infusion times are documented to ensure adherence.

Bendamustine Glenmark is presented as a powder for preparation of a 2.5 mg/mL solution for infusion. The active ingredient, bendamustine hydrochloride, is administered intravenously at a dose of 90 mg/m². Infusions are given on the scheduled days of each cycle, with administration details recorded to verify correct delivery.

A matching placebo tablet, identical in appearance to orelabrutinib, is used only at the randomisation stage. The tablet is not administered during the safety and tolerability phase and therefore has no ongoing dosing schedule. Its use is documented to maintain blinding of the study.

The efficacy of orelabrutinib in combination with rituximab and bendamustine will be evaluated primarily by progression‑free survival (PFS) as determined by an Independent Review Committee (IRC) applying the 2014 International Working Group Criteria for Non‑Hodgkin Lymphoma (iwNHL). Secondary efficacy assessments include overall survival (OS), investigator‑assessed PFS, overall response rate (ORR), complete response rate (CRR), duration of response (DOR), time to response (TTR), and time to next treatment (TTNT). All disease‑specific endpoints will be evaluated according to iwNHL criteria by both the IRC and the investigators. Patient‑reported outcomes will be measured using the FACT‑Lym and EQ‑5D‑5L instruments to capture time to worsening, health‑related quality‑of‑life scores, and changes from baseline. Efficacy data will be collected throughout the treatment period and analyzed in accordance with the predefined statistical analysis plan.