Oral Utidelone Capsule, a First-in-Class Solid Microtubule Stabilizer, in Advanced Breast Cancer: A First-in-Human Phase I-II Trial

Abstract Purpose: Chemotherapy options for advanced breast cancer (ABC), which are usually given intravenously, may have suboptimal tolerability and convenience for long‑term disease management. This first-in-human phase I-II study evaluated the efficacy, safety and pharmacokinetic (PK) profile of utidelone capsule (UTD2), the first oral solid microtubule stabilizer and an oral formulation of the approved microtubule inhibitor utidelone injection (UTD1), as monotherapy and in combination with capecitabine in ABC. Patients and Methods: This multicenter trial (NCT05700084) had three parts. In Part 1, dose-escalation of UTD2 in patients with advanced solid tumors was done to establish the maximum tolerated dose (MTD). Part 2 used a crossover design to compare PK profiles of UTD2 and UTD1 in patients with advanced solid tumors. In Part 3 patients with ABC received UTD2 plus capecitabine. Primary endpoints included the MTD of UTD2 and the objective response rate (ORR) of UTD2 plus capecitabine. Secondary endpoints included PK parameters, progression-free survival (PFS), disease control rate (DCR), and safety. Results: Between August 30, 2023 and May 9, 2025, 82 patients were enrolled. All 10 evaluable patients who received UTD2 monotherapy had ABC; the confirmed ORR was 20.0% and DCR was 70.0%. In the 44 evaluable patients treated with all-oral UTD2 plus capecitabine, the confirmed ORR was 52.3% (95% CI, 36.767.5), median PFS was 8.3 months (95% CI, 5.410.6) and DCR was 88.6% (95% CI, 75.496.2). No dose-limiting toxicities were observed. The absolute oral bioavailability of UTD2 was 31.8%. Grade ≥3 neutropenia occurred in 12% of patients and grade ≥3 peripheral neuropathy in 2%. Conclusion: UTD2 showed promising antitumor efficacy and was well-tolerated. UTD2 plus capecitabine provided clinical benefit in patients with ABC, offering an alternative to intravenous formulations of microtubule stabilizer.