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.
Highlights
DL8, 360 mg/day, was used for the expansion phase and is higher than doses administered in any previous study; it yielded higher plasma Z-endoxifen concentrations
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
Tamoxifen is a member of the selective estrogen receptor modulator (SERM) drug family and is approved by the FDA for the treatment of patients with estrogen receptor-positive (ER+) metastatic breast cancer, for adjuvant therapy of high-risk ER+/progesterone receptorpositive (PR+) breast cancer, and for chemoprevention in women at high risk of developing breast cancer [1, 2]
Summary
Tamoxifen is a member of the selective estrogen receptor modulator (SERM) drug family and is approved by the FDA for the treatment of patients with estrogen receptor-positive (ER+) metastatic breast cancer, for adjuvant therapy of high-risk ER+/progesterone receptorpositive (PR+) breast cancer, and for chemoprevention in women at high risk of developing breast cancer [1, 2]. CYP3A4/5 is the major CYP isoform responsible for the conversion of a large percentage of tamoxifen into N-desmethyltamoxifen (NDM-tamoxifen). CYP2D6 is the only enzyme responsible for converting NDM-tamoxifen into endoxifen [10]. CYP2D6 converts a small percentage of tamoxifen into 4-hydroxy-tamoxifen and into endoxifen [6]. Z-endoxifen is thought to account for a substantial proportion of the clinical activity of tamoxifen [2, 8, 14, 15]. 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
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