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 StreicherJoseph M. Covey, James H. Doroshow, Alice P. Chen

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)268-277
Number of pages10
Issue number4
StatePublished - Feb 16 2021


  • Pharmacokinetics
  • Phase 1
  • Tamoxifen
  • Z-endoxifen

ASJC Scopus subject areas

  • Oncology


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