Phase 1 study of Z-endoxifen in patients with advanced gynecologic, desmoid, and hormone receptor-positive solid tumors
| Autor: | Barry C. Johnson, Esther Mena, Nancy Moore, Cecilia Monge Bonilla, Frank I. Lin, Lamin Juwara, James H. Doroshow, Geraldine O'Sullivan Coyne, Matthew M. Ames, Matthew P. Goetz, Alice P. Chen, M. Liza Lindenberg, Larry Rubinstein, S. Kummar, Howard Streicher, Renee M. McGovern, Joseph M. Covey, Peter L. Choyke, Joel M. Reid, Richard Piekarz, Rachel Bishop, Naoko Takebe, Jerry M. Collins |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Oncology medicine.medical_specialty Z-endoxifen 03 medical and health sciences 0302 clinical medicine Stable Disease Pharmacokinetics Internal medicine Medicine In patient tamoxifen business.industry 030104 developmental biology phase 1 Hormone receptor 030220 oncology & carcinogenesis Pharmacodynamics business pharmacokinetics Tamoxifen Hormone medicine.drug Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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