(P 182) UPDATED RESULTS FROM AN ONGOING PHASE 1B STUDY OF UNESBULIN (PTC596) PLUS DACARBAZINE FOR THE TREATMENT OF PATIENTS WITH ADVANCED LEIOMYOSARCOMA

Objective: Leiomyosarcoma (LMS) is one of the most common subtypes of soft tissue sarcoma and is associated with a high risk of relapse and a poor prognosis for advanced disease. In preclinical LMS models, unesbulin, a microtubule polymerization inhibitor, potentiated the activity of dacarbazine (DTIC) (Jernigan F, et al. Mol Cancer Ther. 2021;20:1846–1857). Here, we report updated safety and efficacy results from a Phase 1b dose escalation study evaluating the combination of unesbulin with DTIC in patients with advanced LMS (NCT03761095).

Methods: In this single-arm, open-label, Phase 1b clinical trial, patients with advanced LMS received unesbulin orally at 200, 300, or 400 mg twice weekly (BIW) in combination with intravenous DTIC at 1,000 mg/m2 once every 21 days. The primary objectives were to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of unesbulin in combination with DTIC and to characterize the safety profile of the combination.
The secondary objectives include the evaluation of antitumor activity of unesbulin in combination with DTIC. The time-to-event continual reassessment model was used for dose finding. A total of 41 patients were enrolled, which included 12 patients in a food-effect expansion cohort.

Results: As of the data cutoff on May 8th, 2023, 41 patients with LMS have been treated. Median prior lines of therapy were 3 with 19 patients (46.3%) receiving 4 or more prior lines of therapy. Twenty patients had non-uterine and 21 patients had uterine LMS. Thirty-three patients received therapy at the RP2D, that was previously determined as 300 mg BIW with DTIC 1,000 mg/m2 every 21 days. The most common treatment-related adverse events included fatigue, diarrhea, anemia, decrease in appetite, nausea, vomiting, and decrease in platelet, neutrophil, white blood cell, and lymphocyte counts. In the patients evaluable for efficacy, the objective response rate (ORR) was 21.6% (8/37) and the disease control rate (DCR) (DCR = complete response + partial response + stable disease at 12 weeks) was 54.1%. At the 300 mg dose level, the ORR was 24.1% (7/29) and the DCR was 55.2%. Patients received a median of five cycles (range 1–28). The study is ongoing, with patients continuing to receive treatment. Updated clinical results will be presented at the 2023 Connective Tissue Oncology Society Congress in Dublin, Ireland.

Conclusion: Unesbulin 300 mg BIW in combination with DTIC 1,000 mg/m2 every 21 days was well tolerated and demonstrated promising efficacy in a heavily pre-treated patient population with advanced LMS; these results support further investigation. A randomized, placebo-controlled, Phase 2/3 trial is ongoing (NCT05269355).