Legubicin

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.

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).

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 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 mg/ m² Q2W and 1 with ovarian cancer receiving legubicin 270 mg/ m² Q3W had a partial response, and the IRC-confirmed objective response rate was 5.7% (95% CI 0.7%-19.2%).

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.

Chinese Clinical Trial Registry (http://www.chictr.org.cn/, ChiCTR2600122142; registered on April 9, 2026).

Legubicin, a novel prodrug based on doxorubicin, has both albumin-binding and legumain-activating properties. The aim of this study was to develop and validate a UHPLC-MS/MS method for investigating the in vivo pharmacokinetics and tissue distribution profiles of legubicin in rats and tumor-bearing mice following intravenous administration, and to compare this prodrug with the positive control drug doxorubicin. The study employed a UHLC-MS/MS method to determine the levels of albumin-bound of legubicin and two metabolites (free Leu-DOX and DOX) in plasma, tumor, and tissue samples. This method was validated for good selectivity, high sensitivity, excellent extraction recovery, and short run time. The results showed that legubicin was present in the circulation in vivo mainly in a protein-bound form with larger AUC values and lower clearance and distribution, and essentially released small amounts of doxorubicin. Compared to administration of equimolar doses of doxorubicin, legubicin showed increased exposure of the active drug in the tumor and decreased the level of the active drug in the heart and kidney. This study provides valuable information on the pharmacokinetics and tissue distribution of legubicin, implicating its potential as a novel and effective drug candidate for anti-cancer therapies.