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

Matthew Philip Goetz, Vera Jean Suman, Joel M Reid, Donald 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 C Haddad, Charles Erlichman, Alex AdjeiDan Collins, Howard Streicher, Zachary R. Chalmers, Garrett Frampton, John R Hawse, James H. Doroshow, Jerry M. Collins

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Abstract

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
Volume35
Issue number30
DOIs
StatePublished - Oct 20 2017

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Tamoxifen
Breast Neoplasms
Maximum Tolerated Dose
Mutation
Cytochrome P-450 CYP2D6
Biopsy
Neoplasms
Aromatase Inhibitors
Embolism
Disease-Free Survival
4-hydroxy-N-desmethyltamoxifen
Appointments and Schedules
Estrogens
Pharmacokinetics
Genotype
Lung
DNA
Serum
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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First-in-human phase I Study of the tamoxifen metabolite Z-endoxifen in women with endocrine-refractory metastatic breast cancer. / Goetz, Matthew Philip; Suman, Vera Jean; Reid, Joel M; Northfelt, Donald W; Mahr, Michael A.; Ralya, Andrew T.; Kuffel, Mary; Visscher, Sarah A.; Kipp, Benjamin R.; Liu, Minetta C; Hawse, John R.; Ames, Matthew M.; Ingle Buhrow, James N.; Safgren, Stephanie L.; McGovern, Renee M.; Black, John; Dockter, Travis; Haddad, Tufia C; Erlichman, Charles; Adjei, Alex; Collins, Dan; Streicher, Howard; Chalmers, Zachary R.; Frampton, Garrett; Hawse, John R; Doroshow, James H.; Collins, Jerry M.

In: Journal of Clinical Oncology, Vol. 35, No. 30, 20.10.2017, p. 3391-3400.

Research output: Contribution to journalArticle

Goetz, MP, Suman, VJ, Reid, JM, Northfelt, DW, Mahr, MA, Ralya, AT, Kuffel, M, Visscher, SA, Kipp, BR, Liu, MC, Hawse, JR, Ames, MM, Ingle Buhrow, JN, Safgren, SL, McGovern, RM, Black, J, Dockter, T, Haddad, TC, Erlichman, C, Adjei, A, Collins, D, Streicher, H, Chalmers, ZR, Frampton, G, Hawse, JR, Doroshow, JH & Collins, JM 2017, 'First-in-human phase I Study of the tamoxifen metabolite Z-endoxifen in women with endocrine-refractory metastatic breast cancer', Journal of Clinical Oncology, vol. 35, no. 30, pp. 3391-3400. https://doi.org/10.1200/JCO.2017
Goetz, Matthew Philip ; Suman, Vera Jean ; Reid, Joel M ; Northfelt, Donald W ; Mahr, Michael A. ; Ralya, Andrew T. ; Kuffel, Mary ; Visscher, Sarah A. ; Kipp, Benjamin R. ; Liu, Minetta C ; Hawse, John R. ; Ames, Matthew M. ; Ingle Buhrow, James N. ; Safgren, Stephanie L. ; McGovern, Renee M. ; Black, John ; Dockter, Travis ; Haddad, Tufia C ; Erlichman, Charles ; Adjei, Alex ; Collins, Dan ; Streicher, Howard ; Chalmers, Zachary R. ; Frampton, Garrett ; Hawse, John R ; Doroshow, James H. ; Collins, Jerry M. / First-in-human phase I Study of the tamoxifen metabolite Z-endoxifen in women with endocrine-refractory metastatic breast cancer. In: Journal of Clinical Oncology. 2017 ; Vol. 35, No. 30. pp. 3391-3400.
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abstract = "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.",
author = "Goetz, {Matthew Philip} and Suman, {Vera Jean} and Reid, {Joel M} and Northfelt, {Donald W} and Mahr, {Michael A.} and Ralya, {Andrew T.} and Mary Kuffel and Visscher, {Sarah A.} and Kipp, {Benjamin R.} and Liu, {Minetta C} and Hawse, {John R.} and Ames, {Matthew M.} and {Ingle Buhrow}, {James N.} and Safgren, {Stephanie L.} and McGovern, {Renee M.} and John Black and Travis Dockter and Haddad, {Tufia C} and Charles Erlichman and Alex Adjei and Dan Collins and Howard Streicher and Chalmers, {Zachary R.} and Garrett Frampton and Hawse, {John R} and Doroshow, {James H.} and Collins, {Jerry M.}",
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TY - JOUR

T1 - First-in-human phase I Study of the tamoxifen metabolite Z-endoxifen in women with endocrine-refractory metastatic breast cancer

AU - Goetz, Matthew Philip

AU - Suman, Vera Jean

AU - Reid, Joel M

AU - Northfelt, Donald W

AU - Mahr, Michael A.

AU - Ralya, Andrew T.

AU - Kuffel, Mary

AU - Visscher, Sarah A.

AU - Kipp, Benjamin R.

AU - Liu, Minetta C

AU - Hawse, John R.

AU - Ames, Matthew M.

AU - Ingle Buhrow, James N.

AU - Safgren, Stephanie L.

AU - McGovern, Renee M.

AU - Black, John

AU - Dockter, Travis

AU - Haddad, Tufia C

AU - Erlichman, Charles

AU - Adjei, Alex

AU - Collins, Dan

AU - Streicher, Howard

AU - Chalmers, Zachary R.

AU - Frampton, Garrett

AU - Hawse, John R

AU - Doroshow, James H.

AU - Collins, Jerry M.

PY - 2017/10/20

Y1 - 2017/10/20

N2 - 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.

AB - 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.

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