Mitoxantrone hydrochloride liposome (Lipo-MIT) combined with capecitabine in HER2-negative advanced breast cancer: a dose-escalation, phase I study.

BACKGROUND: Patients with HER2-negative advanced breast cancer (ABC) have limited chemotherapy options after progression on anthracyclines and taxanes. Mitoxantrone Hydrochloride Liposome (Lipo-MIT), a nanoparticle formulation with a 60-nm particle size, is designed to reduce toxicity and enhance tumor targeting. We investigated the safety and efficacy of Lipo-MIT combined with capecitabine in pretreated HER2-negative ABC. METHODS: In this phase I dose-escalation study, eligible patients were sequentially enrolled to receive escalating doses of Lipo-MIT (ranging from 16 to 24 mg/m2) administered either every 3 weeks (Q3W) or every 4 weeks (Q4W), combined with standard capecitabine. Primary endpoints included dose-limiting toxicities (DLTs) and determination of the recommended phase 2 dose (RP2D). Secondary endpoints assessed safety and preliminary efficacy. RESULTS: Twenty-six patients were enrolled. Lipo-MIT 22 mg/m2 administered Q4W was identified as the RP2D. The combination demonstrated a manageable safety profile, with no reports of severe cardiac toxicity or hand-foot syndrome. Interstitial lung disease was observed in 19.2% of patients, all of which were manageable and low-grade (Grade 1–2). In a post hoc, exploratory analysis, the objective response rate (ORR) was 36.4% in the Q4W cohort and 13.3% in the Q3W cohort. The Q4W regimen yielded a median progression-free survival (mPFS) of 12.7 months (95% CI, 9.3–NR), which was numerically longer than the mPFS of 5.4 months observed in the Q3W cohort, albeit in the context of a sequential design and baseline imbalances. CONCLUSIONS: The combination of Lipo-MIT and capecitabine showed preliminary antitumor activity and manageable tolerability in heavily pretreated HER2-negative ABC. While the Q4W dosing schedule (22 mg/m²) yielded numerically longer PFS, this comparison is based on a non-randomized, sequential cohort design; thus, all inter-cohort efficacy findings are strictly exploratory and hypothesis-generating. Further evaluation in phase II/III trials as a potential later-line strategy. CLINICAL TRIAL REGISTRATION: NCT06156761.