Phase Ib Study of Unesbulin (PTC596) Plus Dacarbazine for the Treatment of Locally Recurrent, Unresectable or Metastatic, Relapsed or Refractory Leiomyosarcoma

Abstract

Purpose: This multicenter, single-arm, open-label, phase Ib study was designed to determine the recommended phase II dose (RP2D) and to evaluate the safety and preliminary efficacy of unesbulin plus dacarbazine (DTIC) in patients with advanced leiomyosarcoma (LMS).

Patients and methods: Adult subjects with locally advanced, unresectable or metastatic, relapsed or refractory LMS were treated with escalating doses of unesbulin orally twice per week in combination with DTIC 1,000 mg/m² intravenously (IV) once every 21 days. The time-to-event continual reassessment method was used to determine the RP2D on the basis of dose-limiting toxicities (DLTs) assessed during the first two 21-day treatment cycles. All explored doses of unesbulin (200 mg up to 400 mg) were in combination with DTIC. An expansion cohort was enrolled to evaluate the safety and efficacy of unesbulin at the RP2D.

Results: Unesbulin 300 mg administered orally twice per week in combination with DTIC 1,000 mg/m² IV once every 21 days was identified as the RP2D. On the basis of data from 27 subjects who were deemed DLT-evaluable, toxicity was higher in the unesbulin 400 mg group, with three of four subjects (75%) experiencing DLTs versus one of four subjects (25%) in the 200 mg group and three of 19 subjects (15.8%) in the 300 mg group. The most commonly reported DLTs and treatment-related grade 3 and 4 adverse events were thrombocytopenia and neutropenia. At the RP2D, seven subjects who were efficacy evaluable achieved partial response for an objective response rate of 24.1%.

Conclusion: Unesbulin 300 mg twice per week plus DTIC 1,000 mg/m² once every 21 days was identified as the RP2D, demonstrating a favorable benefit-risk profile in a heavily pretreated population of adults with advanced LMS.

Trial registration: ClinicalTrials.gov NCT03761095.

FIG 1.

Best tumor reduction and time on treatment by unesbulin (PTC596) dose level—efficacy population. (A) The waterfall plot is best tumor reduction from baseline in sum of diameters of all target lesions in the efficacy population. (B) Swimmer chart depicts time on treatment for the efficacy population. Among the 37 treated subjects, the following subject did not have a percent change of diameter noted: 01-010. Subjects with nonuterine LMS are designated with diagonal lines within the bars. Time on treatment (weeks) was measured as the time in weeks from the first dose date to the last dose date calculated as (last dose date – first dose date + 1). DTIC, dacarbazine; LMS, leiomyosarcoma; PR, partial response; SLD, sum of longest diameters.

FIG 2.

Tumor CT scan at baseline and after 12 cycles of unesbulin in combination with dacarbazine. CT scan of tumor lesions (left lower lobe [top] and right lower lobe [bottom]) from a 61-year-old woman diagnosed with an unresectable 13.5-cm high-grade uterine leiomyosarcoma at baseline (left) and at best response (–43.5%) after approximately 24 weeks of treatment (right). CT, computed tomography.