Liposomal mitoxantrone versus chidamide in relapsed/refractory peripheral T-cell lymphoma: Final analysis from the multicenter, prospective randomized phase 3 study

Abstract Background Outcomes for patients with relapsed/refractory (R/R) peripheral T-cell lymphomas (R/R-PTCLs) are poor. Single agent overall response rates (ORRs) for R/R-PTCLs generally fall within the 20-35% range, with a median progression-free survival (PFS) of less than 4 months. Thus, there is an urgent need for more effective therapies that can provide deep remissions or long-term disease control. Liposomal mitoxantrone (Lipo-MIT, manufactured by CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.) monotherapy exhibited promising and durable antitumor activity in phase 2 study. This study was designed to evaluate the efficacy and safety of Lipo-MIT versus chidamide (an oral subtype-selective histone deacetylase inhibitor) in this population. Methods This study is an open-label, active-controlled, randomized phase 3 study (ClinicalTrials.gov identifier NCT04668690). Eligible patients from 32 sites in China with R/R-PTCLs were randomly assigned 1:1 to receive either Lipo-MIT (20 mg/m², IV, Q4W, for a maximum of 6-8 cycles) or chidamide (30 mg, twice weekly). Patients who failed from chidamide were permitted to crossover to the Lipo-MIT group. The primary endpoint was PFS assessed by the Independent Review Committee (IRC) in the intention-to-treat (ITT) population. Secondary endpoints included, but not limited to, PFS assessed by investigators, ORR, complete response (CR) rate, overall survival (OS), and safety. Results From April 2021 to October 2024, a total of 193 patients were enrolled and randomly assigned to Lipo-MIT (n=97) or chidamide (n=96) groups. Baseline characteristics were essentially balanced between the two groups, including AITL, PTCL-NOS, and ENKTCL subtypes. A total of 190 patients received at least one dose of study drug (Lipo-MIT n=95; chidamide n=95; safety population). At median follow-up of 11.1 months in the Lipo-MIT group and 8.4 months in the chidamide group, the median PFS per IRC was 7.5 months (95% CI: 4.2-12.0) in the Lipo-MIT group and 2.6 months (95% CI: 1.9-3.7) in the chidamide group (hazard ratio [HR] 0.58, 95% CI: 0.41-0.81; P = 0.0008). Similar results were obtained assessed by the investigators (7.6 vs 2.5 months, HR 0.63, 95% CI: 0.45-0.88; P = 0.0035). Twenty-seven patients (28.1%) in the chidamide group crossed over to the Lipo-MIT group. Median OS was 14.0 months (95% CI: 10.8-23.4) with Lipo-MIT versus 8.8 months (95% CI: 7.2-11.6) with chidamide (HR 0.78, 95% CI: 0.54-1.13). The 18-month OS rates were 45.4% (95% CI: 34.2-56.0) in the Lipo-MIT group and 35.3% (95% CI: 25.2-45.5) in the chidamide group, respectively. Both PFS and OS were generally consistent across key subgroups. The CR rate and ORR were significantly higher in the Lipo-MIT group than in the chidamide group (CR rate, 13.4% vs 7.3%; ORR, 36.1% vs 18.8%). The incidences of grade 3 or higher treatment-emergent adverse event (TEAEs) and serious AEs (SAEs) were similar between groups (78.9% vs 81.1% and 43.2% vs 45.3%). A higher incidence of leukopenia (any grade) was reported in the Lipo-MIT group (85.3%) than in the chidamide group (69.5%). Thrombocytopenia (any grade) was more common in the chidamide group (57.9% vs 78.9%). The incidence of cardiotoxicity (any grade) was comparable between the two groups (21.1% vs 30.5%), with most events being grade 1-2. Treatment discontinuations due to AEs were 15.8% vs 14.7%. Conclusion The study met its primary efficacy endpoint. The outcome of the present phase 3 trial demonstrated that the efficacy of Lipo-MIT was superior to chidamide with an acceptable and manageable overall safety profile in patients with R/R PTCL.