First-in-human phase I Study of the tamoxifen metabolite Z-endoxifen in women with endocrine-refractory metastatic breast cancer

Matthew P. Goetz, Vera J. Suman, Joel M. Reid, Don W. Northfelt, Michael A. Mahr, Andrew T. Ralya, Mary Kuffel, Sarah A. Visscher, Benjamin R. Kipp, Minetta C. Liu, John R. Hawse, Matthew M. Ames, James N. Ingle Buhrow, Stephanie L. Safgren, Renee M. McGovern, John Black, Travis Dockter, Tufia Haddad, Charles Erlichman, Alex A. AdjeiDan Collins, Howard Streicher, Zachary R. Chalmers, Garrett Frampton, John R. Hawse, James H. Doroshow, Jerry M. Collins

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


Purpose Endoxifen is a tamoxifen metabolite with potent antiestrogenic activity. Patients and Methods We performed a phase I study of oral Z-endoxifen to determine its toxicities, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity. Eligibility included endocrine-refractory, estrogen receptor–positive metastatic breast cancer. An accelerated titration schedule was applied until moderate or dose-limiting toxicity occurred, followed by a 3+3 design and expansion at 40, 80, and 100 mg per day. Tumor DNA from serum (circulating cell free [cf); all patients] and biopsies [160 mg/day and expansion]) was sequenced. Results Of 41 enrolled patients, 38 were evaluable for MTD determination. Prior endocrine regimens during which progression occurred included aromatase inhibitor (n = 36), fulvestrant (n = 21), and tamoxifen (n = 15). Patients received endoxifen once daily at seven dose levels (20 to 160 mg). Dose escalation ceased at 160 mg per day given lack of MTD and endoxifen concentrations . 1,900 ng/mL. Endoxifen clearance was unaffected by CYP2D6 genotype. One patient (60 mg) had cycle 1 dose-limiting toxicity (pulmonary embolus). Overall clinical benefit rate (stable . 6 months [n = 7] or partial response by RECIST criteria [n = 3]) was 26.3% (95% CI, 13.4% to 43.1%) including prior tamoxifen progression (n = 3). cfDNA mutations were observed in 13 patients (PIK3CA [n = 8], ESR1 [n = 5], TP53 [n = 4], and AKT [n = 1]) with shorter progression-free survival (v those without cfDNA mutations; median, 61 v 132 days; log-rank P = .046). Clinical benefit was observed in those with ESR1 amplification (tumor; 80 mg/day) and ESR1 mutation (cfDNA; 160 mg/day). Comparing tumor biopsies and cfDNA, some mutations (PIK3CA, TP53, and AKT) were undetected by cfDNA, whereas cfDNA mutations (ESR1, TP53, and AKT) were undetected by biopsy. Conclusion In endocrine-refractory metastatic breast cancer, Z-endoxifen provides substantial drug exposure unaffected by CYP2D6 metabolism, acceptable toxicity, and promising antitumor activity.

Original languageEnglish (US)
Pages (from-to)3391-3400
Number of pages10
JournalJournal of Clinical Oncology
Issue number30
StatePublished - Oct 20 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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