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The Desmoid Tumor Research Foundation

February 2021

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

Author Information

Takebe N(1), O'Sullivan Coyne G(1), Kummar S(1,2), Collins J(1), Reid JM(3), Piekarz R(1), Moore N(1), Juwara L(4), Johnson BC(4), Bishop R(5), Lin FI(6), Mena E(6), Choyke PL(6), Lindenberg ML(6), Rubinstein LV(7), Monge Bonilla C(8), Goetz MP(3), Ames MM(3), McGovern RM(3), Streicher H(1), Covey JM(1), Doroshow JH(1,8), Chen AP(1).

(1)Div of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD.(2)Div of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR. (3)Dept of Oncology, Mayo Clinic, Rochester, MN. (4)Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD. (5)Consult Services Section, National Eye Institute, Bethesda, MD. (6)Molecular Imaging Program, National Cancer Institute, Bethesda, MD. (7)Biometric Research Program, National Cancer Institute, Bethesda, MD. (8)Center for Cancer Research, National Cancer Institute, Bethesda, MD.

Publication

Oncotarget

Summary

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. 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). 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). 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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