Safety and Efficacy of the Combination Lurbinectedin plus Doxorubicin from a Phase 1b Trial in Patients with Advanced/Metastatic Soft-Tissue Sarcoma.

Autor:	Cote GM; Center for Sarcoma and Connective Tissue Oncology, Mass General Cancer Center, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Haddox CL; Harvard Medical School, Boston, Massachusetts.; Sarcoma Division, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Choy E; Center for Sarcoma and Connective Tissue Oncology, Mass General Cancer Center, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Merriam PA; Harvard Medical School, Boston, Massachusetts., Mazzola E; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Venkataraman V; Harvard Medical School, Boston, Massachusetts.; Sarcoma Division, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Alcindor T; Harvard Medical School, Boston, Massachusetts.; Sarcoma Division, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Wagner AJ; Harvard Medical School, Boston, Massachusetts.; Sarcoma Division, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Demetri GD; Harvard Medical School, Boston, Massachusetts.; Sarcoma Division, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Ludwig Center at Harvard, Boston, Massachusetts.; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Boston, Massachusetts., George S; Harvard Medical School, Boston, Massachusetts.; Sarcoma Division, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Jul 01; Vol. 30 (13), pp. 2702-2708.
DOI:	10.1158/1078-0432.CCR-24-1037
Abstrakt:	Purpose: While cytotoxic chemotherapy is the standard first-line treatment for patients with metastatic soft-tissue sarcoma (STS), clinical outcomes remain suboptimal. Our prior study showed lurbinectedin plus doxorubicin is well tolerated with promising clinical activity in STS. We designed this phase 1b trial to optimize dosing as the basis for a randomized trial in leiomyosarcoma and to further explore the safety profile and efficacy signal. Patients and Methods: Patients had advanced/metastatic STS and no prior anthracycline/lurbinectedin/trabectedin. Escalation followed a 3 + 3 design with 3-week cycles: lurbinectedin (3.2 mg/m2 day 1) and two doxorubicin levels (DL1, 25 mg/m2 day 1; DL2, 25 mg/m2 days 1 and 8). The primary objectives were to identify the maximum tolerated dose and recommended dose for subsequent randomized trials. Results: Ten patients were enrolled in a 6-month period. The most common treatment-emergent adverse events were grade (G) 2 fatigue and nausea, and G2 cytopenias with no febrile neutropenia events. There were two dose-limiting toxicities (DLTs) at DL2 [day 8 (G2 alanine aminotransferase [ALT]/aspartate aminotransferase increase, G3 neutropenia)], and one DLT in DL1 (G3 ALT increase). These were reversible and all patients continued the study. DL1 was chosen for further study. At the time of data cutoff, the estimated median progression-free survival is 16.5 months [95% confidence interval (CI), 6.0-ND]. The objective response rate was 60% (6/10 confirmed partial responses). Conclusions: In this phase 1b study, the recommended dose is lurbinectedin 3.2 mg/m2 in combination with doxorubicin 25 mg/m2 every 3 weeks. The study combination was well tolerated and demonstrated intriguing clinical activity. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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