Efficacy and safety results of a multi-center phase I study of utidelone capsule, a novel oral microtubule inhibitor, in advanced solid tumor patients.

3030 Background: Utidelone is a novel microtubule inhibitor, whose injectable formulation (UTD1) has been approved for advanced breast cancer in China since 2021. Attempts to develop oral microtubule inhibitor have not made significant progress; no oral microtubule inhibitors have been approved in the United States to date. Utidelone is insusceptible to P-glycoprotein-mediated efflux, thereby optimizing it for oral administration on an intermittent schedule. Utidelone capsule (UTD2) can significantly improve medication compliance and the convenience of clinical application. This is the first-in-human study of UTD2, and the trial has been completed with final results presented here. Methods: Eligible patients were aged ≥18, with an ECOG PS of 0-1, life expectancy ≥12weeks, pathologically confirmed advanced solid tumor refractory to prior standard therapies. Patients were treated with UTD2 monotherapy. The starting dose was 5-day 25 mg/m 2 /d for 2 patients, with planned escalation to 5-day 50, 75, 100 mg/m 2 /d and 7-day 70 mg/m 2 /d for 2, 6, 3 and 2 patients, repectively in a 21-day cycle. The primary objective was to determine DLT and the MTD. Secondary objectives included efficacy, PK profile and RP2D. Results: 18 advanced solid tumor patients were enrolled (3 didn’t complete DLT observation) with median age of 60.8 years (range 29.0-81.0), 9 females and 9 males. All patients had received prior treatment in advanced settings with maximal 9 lines. Two DLTs of Grade 3 and Grade 4 diarrhea occurred, one at 5-day 100 mg/m 2 /d and one at 7-day 70 mg/m 2 /d. Considering the total dose per cycle for both cohorts were similar, the MTD was determined to be 5-day 75 mg/m 2 /d via SMC. 11 patients were evaluated for efficacy with an outcome of 1 CR (ovarian cancer), 1 PR (ovarian cancer), 7 SD (testicular Sertoli cell tumor, NSCLC*2, pancreatic adenocarcinoma*2, appendiceal adenocarcinoma and soft tissue sarcoma), with the longest DoT of 12 cycles. The ORR was 18.2% and the CBR was 81.8%. PK results showed that the characteristics of utidelone were consistent with a two-compartment model. Compared to single-dose administration, there was no accumulation of utidelone in plasma upon multi-dose. The most frequent TEAEs were Grade 1/2, including diarrhea, fatigue, nausea, peripheral sensory neuropathy, vomiting, and decreased appetite (≥20% incidence rate), which recovered with supportive treatments. The ≥Grade 3 TRAE included diarrhea (27.8%) and fatigue (5.6%). Conclusions: This completed study demonstrates encouraging anti-tumor activity with manageable safety of UTD2 in patients with heavily pre-treated advanced solid tumors. The results support continuing development of UTD2 for the upcoming phase II/III studies for gastric and ovarian cancers. Clinical trial information: NCT05681000 .