NCT07272499

Orelabrutinib Plus Lisaftoclax and Rituximab in Untreated Mantle Cell Lymphoma With High-Risk Disease

A Prospective, Multicenter, Open-Label Clinical Study of Orelabrutinib Plus Lisaftoclax and Rituximab in Treatment-Naive, High-Risk Mantle Cell Lymphoma (MCL)

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 25 (estimated)
• Sponsor: Ruijin Hospital · Academic / Other
• Sex: All
• Age: 14 Years
• Healthy volunteers: Not accepted

Summary

This multicenter, open-label, trial aims to evaluate the efficacy and safety of orelabrutinib plus lisaftoclax and rituximab in patients with high-risk mantle cell lymphoma (MCL). The primary objective is to assess the optimal complete response (CR) rate during the induction phase, with secondary objectives including progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety. Exploratory analysis will investigate the correlation between tumor biomarkers and treatment efficacy.

Detailed description

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy accounting for 2-10% of non-Hodgkin lymphomas, primarily affecting middle-aged and elderly individuals. Conventional immunochemotherapy often yields suboptimal outcomes in high-risk subtypes, such as those with blastoid variant morphology, high MIPI score, Ki-67 \>30%, TP53 abnormalities, or complex karyotype . Over the past decade, the approval of targeted agents has introduced novel combination regimens, offering new therapeutic avenues for these patients. The SYMPATICO trial demonstrated that ibrutinib combined with venetoclax significantly prolonged progression-free survival (PFS) in patients with relapsed/refractory (R/R) MCL compared to placebo after a median follow-up of 51.2 months. Subgroup analysis revealed a pronounced benefit in TP53-mutated patients (HR 0.57, 95% CI 0.33-0.97). Among 74 TP53-mutated patients receiving the combination, median PFS was 20.9 months, with a complete response (CR) rate of 57% and a duration of CR of 32.2 months. The BoVen regimen (BTK inhibitor + obinutuzumab + venetoclax) reported a CR rate of 88% in 25 treatment-naïve TP53-mutated MCL patients. After a median follow-up of 28.2 months, the 2-year PFS rate was 72%, outperforming outcomes in the SYMPATICO TP53-mutant cohort. These results underscore the promise of combining BTK inhibitor, anti-CD20 antibody, and Bcl-2 inhibitor, not only for TP53-mutant high-risk groups but potentially for a broader patient population. Lisaftoclax is a next-generation Bcl-2 inhibitor with efficacy comparable to venetoclax but featuring an improved safety profile and more convenient dosing. It has been approved in China and is currently in international Phase III trials for CLL/SLL, MDS, and AML. Orelabrutinib is a novel, highly selective BTK inhibitor associated with reduced off-target effects and enhanced safety. Large-scale, non-head-to-head safety comparisons suggest it has a favorable safety standing in its class. Therefore, this study is planned to evaluate the efficacy and safety of orelabrutinib in combination with lisaftoclax and rituximab for high-risk MCL. High-risk factors include blastoid/pleomorphic variant, TP53 mutation/loss or p53 protein expression \>50%, Ki-67 ≥30%, and high-risk MIPI status.

Conditions

• Mantle Cell Lymphoma (MCL)

Interventions

Type	Name	Description
DRUG	Orelabrutinib	150mg/day PO once daily
DRUG	Rituximab (R)	375 mg/m² IV on day 1/cycle
DRUG	Lisaftoclax (APG-2575)	Cycle1(100mg day1, 200mg day2, 400mg day3, 600mg/day day4-28), Cycle2-6 600mg/day, PO once daily.
DRUG	Lisaftoclax (APG-2575)	600mg/day, PO once daily

Timeline

• Start date: 2025-09-10
• Primary completion: 2028-09-10
• Completion: 2028-09-10
• First posted: 2025-12-09
• Last updated: 2025-12-09

Locations

1 site across 1 country: China