A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study Evaluating the Efficacy and Safety of Orelabrutinib Plus R-CHOP Versus Placebo Plus R-CHOP in Treatment-Naïve Patients with Mcd Subtype Diffuse Large B-Cell Lymphoma

Background: Diffuse large B-cell lymphomas (DLBCLs) are heterogeneous diseases including genetic subtypes that have distinct gene expression profiles, immune microenvironments, and outcomes following immunochemotherapy. LymphGen algorithm classified DLBCL into 7 genetic subtypes: MCD, N1, BN2, ST2, A53, EZB (MYC+) and EZB (MYC-). Newly diagnosed DLBCL patients with different subtypes had distinct responses to the standard immunochemotherapy. Among those subgroups, patients with the MCD subtype reported the poorest prognosis with a 5-year overall survival (OS) rate of 40%. MCD subtype acquires mutations that promote chronic active BCR signaling, which can be targeted by Bruton tyrosine kinase inhibitors (BTKi). Orelabrutinib, a second-generation BTKi, was designed to have fewer off-target activities and improved efficacy and safety. Orelabrutinib is a potent (IC50 1.6 nM), irreversible BTK inhibitor with high selectivity for BTK and a sustained BTK occupancy for 24h post dose. In December 2020, orelabrutinib monotherapy received its first approval in China for the superior clinical activity in Chinese patients with relapse/refractory mantle cell lymphoma (NCT03494179) and chronic lymphocytic leukemia (NCT03493217). Orelabrutinib was generally well tolerated in clinical trials of B-cell lymphoma. With the superior safety and efficacy profiles, orelabrutinib is potential to fulfill the unmet medical need of patients with MCD subtype. The study described herein is designed to evaluate the safety and efficacy of orelabrutinib combined with R-CHOP regimen versus placebo with R-CHOP in the treatment of treatment-naïve patients with MCD subtype DLBCL.

Methods: This ongoing phase 3, randomized, double-blind, placebo-controlled study will enroll approximately 150 patients to be randomized 1:1, stratified by IPI score (2 vs 3-5). Patients will be treated for 6-8 cycles with 21 days per cycle. In the experimental arm, patients will receive 150 mg of oral orelabrutinib once daily with R-CHOP (rituximab 375 mg/m² intravenously [IV], cyclophosphamide 750 mg/m² IV, doxorubicin 50 mg/m² IV, vincristine 1.4 mg/m2 [max 2mg] IV, and prednisone orally on day 1 of each cycle) every 3 weeks for 6-8 cycles or until disease progression, unacceptable toxicity, or withdrawal of consent. In the control arm, patients will receive placebo with R-CHOP at the same schedule. Eligible patients must have histopathologically confirmed CD20 positive DLBCL with MCD genetic subtype and be aged 18-80 years with defined medical conditions (IPI≥2; Ann Arbor stage II-IV or stage I with bulky lesion ⌀ >7.5cm; Eastern Cooperative Oncology Group [ECOG] score of 0-2). Disease response will be assessed per the 2014 Lugano Classification for non-Hodgkin lymphoma. The co-primary endpoints are progression-free survival (PFS) and the complete response rate (CRR) at the completion of combination therapy both determined by IRC. Key secondary end points include CRR and PFS by investigator assessment, ORR, ORR at the completion of combination therapy, duration of response (DOR), OS, and safety. Recruitment is ongoing.

Fan:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Tian:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Tang:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhang:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhou:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhao:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment, Current equity holder in publicly-traded company.