First-in-Human Phase I Study of the Tamoxifen Metabolite Z-Endoxifen in Women With Endocrine-Refractory Metastatic Breast Cancer
Autor: | James H. Doroshow, DW Visscher, Matthew P. Goetz, Stephanie L. Safgren, Vera J. Suman, Andrew T. Ralya, Michael A. Mahr, Tufia C. Haddad, James N. Ingle, Benjamin R. Kipp, Jerry M. Collins, Joel M. Reid, Charles Erlichman, Zachary R. Chalmers, Garrett M. Frampton, Alex A. Adjei, John R. Hawse, Don W. Northfelt, Travis J. Dockter, Minetta C. Liu, Mary J. Kuffel, Sarah A. Buhrow, Matthew M. Ames, John L. Black, Howard Streicher, Renee M. McGovern |
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Rok vydání: | 2017 |
Předmět: |
Adult
0301 basic medicine Oncology Cancer Research medicine.medical_specialty CYP2D6 Class I Phosphatidylinositol 3-Kinases medicine.drug_class Administration Oral Breast Neoplasms Pharmacology Disease-Free Survival 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Internal medicine Biopsy medicine Humans Neoplasm Metastasis Fulvestrant Aged Aged 80 and over Aromatase inhibitor Dose-Response Relationship Drug Estradiol medicine.diagnostic_test Aromatase Inhibitors business.industry Estrogen Antagonists DNA Neoplasm Middle Aged medicine.disease Metastatic breast cancer Tamoxifen 030104 developmental biology Cytochrome P-450 CYP2D6 Drug Resistance Neoplasm Area Under Curve 030220 oncology & carcinogenesis Mutation Toxicity Female business medicine.drug |
Zdroj: | Journal of Clinical Oncology. 35:3391-3400 |
ISSN: | 1527-7755 0732-183X |
Popis: | 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. |
Databáze: | OpenAIRE |
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