Research Papers:

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

Naoko Takebe, Geraldine O'Sullivan Coyne, Shivaani Kummar, Jerry Collins, Joel M. Reid, Richard Piekarz, Nancy Moore, Lamin Juwara, Barry C. Johnson, Rachel Bishop, Frank I. Lin, Esther Mena, Peter L. Choyke, M. Liza Lindenberg, Larry V. Rubinstein, Cecilia Monge Bonilla, Matthew P. Goetz, Matthew M. Ames, Renee M. McGovern, Howard Streicher, Joseph M. Covey, James H. Doroshow and Alice P. Chen _

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Oncotarget. 2021; 12:268-277. https://doi.org/10.18632/oncotarget.27887

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Naoko Takebe1, Geraldine O'Sullivan Coyne1, Shivaani Kummar1,8, Jerry Collins1, Joel M. Reid2, Richard Piekarz1, Nancy Moore1, Lamin Juwara3, Barry C. Johnson3, Rachel Bishop4, Frank I. Lin5, Esther Mena5, Peter L. Choyke5, M. Liza Lindenberg5, Larry V. Rubinstein6, Cecilia Monge Bonilla7, Matthew P. Goetz2, Matthew M. Ames2, Renee M. McGovern2, Howard Streicher1, Joseph M. Covey1, James H. Doroshow1,7 and Alice P. Chen1

1 Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA

2 Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA

3 Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA

4 Consult Services Section, National Eye Institute, Bethesda, MD 20892, USA

5 Molecular Imaging Program, National Cancer Institute, Bethesda, MD 20892, USA

6 Biometric Research Program, National Cancer Institute, Bethesda, MD 20892, USA

7 Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA

8 Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA

Correspondence to:

Alice P. Chen,email: [email protected]

Keywords: Z-endoxifen; phase 1; tamoxifen; pharmacokinetics

Received: September 30, 2020     Accepted: January 19, 2021     Published: February 16, 2021

Copyright: © 2021 Takebe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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.

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