Background <p>This first-in-human, phase 1a/b dose escalation and expansion trial investigated the safety and antitumor activities of legubicin, a novel conjugate of doxorubicin with a legumain-cleavable tetrapeptide linker, for patients with advanced solid tumors who failed or had no applicable standard of care treatment.</p> Methods <p>Eligible patients received legubicin over 7 dose levels from 20 mg/m² to 360 mg/m² every 3 weeks (Q3W) in phase 1a and legubicin 270 mg/m² every 2 weeks (Q2W) on day 1 and 15 of each 4-week cycle or legubicin 270 mg/m² Q3W on day 1 of each 3-week cycle in phase 1b. The primary endpoints included safety (phase 1a/b), the maximum tolerated dose and recommended phase 2 dose (RP2D) (phase 1a), and independent review committee (IRC)-assessed antitumor activities of legubicin per RECIST version 1.1 (phase 1b).</p> Results <p>Phase 1a enrolled 28 patients (median age 57.5 years; men 60.7% [17/28]) and phase 1b enrolled 35 (median age 53.0 years, men 51.4% [18/35]), with 15 in the 270 mg/m² Q2W cohort and 20 in the 270 mg/m² Q3W cohort. All patients received prior antitumor therapy and 32 (91.4%) in phase 1b received ≥ 3 prior lines of therapy. All patients in phase 1a had any-grade treatment-emergent adverse events (TEAEs), including grade 3 or worse TEAEs in 35.7% (10/28). No maximum tolerated dose was established; the RP2D of legubicin was 270&#xa0;mg/ m² Q2W or Q3W. Thirty-four patients (97.1%) in phase 1b had any-grade TEAEs. Grade 3 or worse TEAEs occurred in 37.1% (13/35) of the patients, including neutrophil count decreased (25.7% [9/35]), leucocyte count decreased (20.0% [7/35]), and anemia (11.4% [4/35]). At the phase 1b data cutoff, 1 patient with lung cancer receiving legubicin 270&#xa0;mg/ m² Q2W and 1 with ovarian cancer receiving legubicin 270&#xa0;mg/ m² Q3W had a partial response, and the IRC-confirmed objective response rate was 5.7% (95% CI 0.7%-19.2%).</p> Conclusions <p>Legubicin is safe and well tolerated at a dose of 270 mg/m² administered every 2 or 3 weeks, with preliminary signals of antitumor activities in a heterogeneous cohort of patients with pretreated advanced tumors, including heavily pretreated lung cancer patients. These findings support further evaluation in tumor‑specific studies.</p> Trial registration <p>Chinese Clinical Trial Registry (<a href="http://www.chictr.org.cn/">http://www.chictr.org.cn/</a>, ChiCTR2600122142; registered on April 9, 2026).</p>