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Phase 1 study of Z-endoxifen in patients with advanced gynecologic, desmoid, and hormone receptor-positive solid tumors

Background: Differential responses to tamoxifen may be due to inter-patient variability in tamoxifen metabolism into pharmacologically active Z-endoxifen. Z-endoxifen administration was anticipated to bypass these variations, increasing active drug levels, and potentially benefitting patients respon...

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Detalles Bibliográficos
Autores principales: Takebe, Naoko, Coyne, Geraldine O'Sullivan, Kummar, Shivaani, Collins, Jerry, Reid, Joel M., Piekarz, Richard, Moore, Nancy, Juwara, Lamin, Johnson, Barry C., Bishop, Rachel, Lin, Frank I., Mena, Esther, Choyke, Peter L., Lindenberg, M. Liza, Rubinstein, Larry V., Bonilla, Cecilia Monge, Goetz, Matthew P., Ames, Matthew M., McGovern, Renee M., Streicher, Howard, Covey, Joseph M., Doroshow, James H., Chen, Alice P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899551/
https://www.ncbi.nlm.nih.gov/pubmed/33659039
http://dx.doi.org/10.18632/oncotarget.27887
Descripción
Sumario:Background: Differential responses to tamoxifen may be due to inter-patient variability in tamoxifen metabolism into pharmacologically active Z-endoxifen. Z-endoxifen administration was anticipated to bypass these variations, increasing active drug levels, and potentially benefitting patients responding sub-optimally to tamoxifen. Materials and Methods: Patients with treatment-refractory gynecologic malignancies, desmoid tumors, or hormone receptor-positive solid tumors took oral Z-endoxifen daily with a 3+3 phase 1 dose escalation format over 8 dose levels (DLs). Safety, pharmacokinetics/pharmacodynamics, and clinical outcomes were evaluated. Results: Thirty-four of 40 patients were evaluable. No maximum tolerated dose was established. DL8, 360 mg/day, was used for the expansion phase and is higher than doses administered in any previous study; it also yielded higher plasma Z-endoxifen concentrations. Three patients had partial responses and 8 had prolonged stable disease (≥ 6 cycles); 44.4% (8/18) of patients at dose levels 6–8 achieved one of these outcomes. Six patients who progressed after tamoxifen therapy experienced partial response or stable disease for ≥ 6 cycles with Z-endoxifen; one with desmoid tumor remains on study after 62 cycles (nearly 5 years). Conclusions: Evidence of antitumor activity and prolonged stable disease are achieved with Z-endoxifen despite prior tamoxifen therapy, supporting further study of Z-endoxifen, particularly in patients with desmoid tumors.