Doublet for Previously Treated Patients With Advanced Leiomyosarcoma

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In a phase Ib study reported in the Journal of Clinical Oncology, Van Tine et al established the recommended phase II dose of oral unesbulin in combination with dacarbazine for patients with locally recurrent, unresectable or metastatic, relapsed or refractory leiomyosarcoma.

Unesbulin is a small molecule that binds to a unique site within the colchicine-binding region of tubulin that results in destabilization of tubulin polymers and microtubules.

Study Details

Forty-one patients were enrolled in the U.S. multicenter trial between April 2019 and October 2022. Patients received twice-weekly unesbulin at 200 mg (n = 4), 300 mg (n = 33), and 400 mg (n = 4) in combination with dacarbazine at 1,000 mg/m2 every 21 days. Dose-limiting toxicities were assessed during the first two treatment cycles. Overall, 30 patients (73%) had received three or more prior therapies.

Key Findings

Unesbulin at 300 mg twice weekly in combination with dacarbazine was selected as the recommended phase II dose for the combination.

Among 27 patients considered dose-limiting toxicity–evaluable, dose-limiting toxicities occurred in 3 of the 4 patients in the 400-mg unesbulin group, 1 of 4 in the 200-mg group, and 3 (15.8%) of 19 in the 300-mg group. All dose-limiting toxicities were grade 3 or 4 thrombocytopenia or neutropenia, except for sepsis and gastric perforation in one patient each in the 300-mg group.

Among all patients, grade 3 or 4 adverse events occurred in 85.4%, most commonly decreased neutrophils (51.2%), decreased platelets (46.3%), decreased white blood cell count (31.7%), anemia (24.4%), and decreased lymphocytes count (22.0%). In the unesbulin 300-mg group, additional grade 3 adverse events occurring in more than one patient were fatigue (12.1%) and diarrhea (6.1%). No treatment-related deaths were reported.

Among all 37 patients evaluable for efficacy, objective response was observed in 8 (21.6%), and the disease control rate (including stable disease for ≥ 3 months) was 54.1%. Among 29 patients in the unesbulin 300-mg group evaluable for efficacy, objective response was observed in 7 (24.1%), and the disease control rate was 55.2%.

The investigators concluded: “Unesbulin [at] 300 mg twice per week plus dacarbazine [at] 1,000 mg/m2 once every 21 days was identified as the recommended phase II dose, demonstrating a favorable benefit-risk profile in a heavily pretreated population of adults with advanced leiomyosarcoma.”

Gary K. Schwartz, MD, of Case Western Reserve University, Cleveland, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by PTC Therapeutics, Inc, and a grant from the Wellcome Trust. For full disclosures of the study authors, visit

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