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

  • Oncotarget. 2021 Feb 16;12(4):268-277. doi: 10.18632/oncotarget.27887.
Naoko Takebe  1 ,  Geraldine O'Sullivan Coyne  1 ,  Shivaani Kummar  1  2 ,  Jerry Collins  1 ,  Joel M Reid  3 ,  Richard Piekarz  1 ,  Nancy Moore  1 ,  Lamin Juwara  4 ,  Barry C Johnson  4 ,  Rachel Bishop  5 ,  Frank I Lin  6 ,  Esther Mena  6 ,  Peter L Choyke  6 ,  M Liza Lindenberg  6 ,  Larry V Rubinstein  7 ,  Cecilia Monge Bonilla  8 ,  Matthew P Goetz  3 ,  Matthew M Ames  3 ,  Renee M McGovern  3 ,  Howard Streicher  1 ,  Joseph M Covey  1 ,  James H Doroshow  1  8 ,  Alice P Chen  1
Affiliations
  • 1. Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA.
  • 2. Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
  • 3. Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
  • 4. Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
  • 5. Consult Services Section, National Eye Institute, Bethesda, MD 20892, USA.
  • 6. Molecular Imaging Program, National Cancer Institute, Bethesda, MD 20892, USA.
  • 7. Biometric Research Program, National Cancer Institute, Bethesda, MD 20892, USA.
  • 8. Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
PMID: 33659039 DOI: 10.18632/oncotarget.27887
Abstract

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.

Keywords
Z-endoxifen; pharmacokinetics; phase 1; tamoxifen.
Products