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

作者：Brian A. Van Tine, Matthew Ingham, Steven Attia, Christian F. Meyer, John D. Baird, Esther M. Brooks-Asplund, Dhiren D'Silva, Ronald Kong, Anthony Mwatha, Kylie O’Keefe, Marla Weetall, Robert J. Spiegel, Gary K. Schwartz · 发表于：Journal of Clinical Oncology · 年份：2024 · DOI：10.1200/jco.23.01684 · 被引用次数：10 · 研究领域：Sarcoma Diagnosis and Treatment、Uterine Myomas and Treatments、Beetle Biology and Toxicology Studies

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/m 2 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/m 2 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 achiev...