Pharmacological Study of Z-endoxifen in Patients with Advanced Tumors

In this phase 1 clinical study, the safety, tolerability, and efficacy of daily oral doses of Z-endoxifen (up to 360 milligrams) were examined in a cohort of patients with gynecologic tumors, desmoid tumors, hormone receptor-positive breast cancer, and other hormone receptor-positive solid tumors.

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Tamoxifen—an estrogen modulating drug that is frequently used to treat breast cancer—has demonstrated effects of differential responses in patients. Researchers believe these differential responses are likely produced due to variations in patient metabolism of tamoxifen into endoxifen. Endoxifen is the active metabolite in tamoxifen. It reduces DNA synthesis by inhibiting estradiol from binding to estrogen receptors. Of their two isomers, the Z-isomers of both endoxifen and 4-hydroxy-tamoxifen are more active than the E-isomers and demonstrate similar levels of anti-estrogenic activity. 

“Z-endoxifen is therefore thought to account for a substantial proportion of the clinical activity of tamoxifen [2, 8, 14, 15].”

In order for tamoxifen to be converted into endoxifen, tamoxifen relies on CYP2D6 enzyme activity. The activity of CYP2D6 can vary among patients due to the numerous genetic polymorphisms in CYP2D6. After receiving tamoxifen, patients that display decreased CYP2D6 activity also show lower levels of endoxifen. Researchers have proposed that directly administering endoxifen to bypass the CYP2D6 route may provide improved results in patients responding poorly to tamoxifen. 

“More than 100 polymorphisms in CYP2D6 have been reported and linked to variations in endoxifen levels following administration of tamoxifen [21, 22].”

Researchers from the National Cancer Institute, National Eye Institute, Mayo Clinic, Frederick National Laboratory for Cancer Research, and Oregon Health & Science University conducted a phase 1 clinical study to examine the safety and tolerability of Z-endoxifen administered directly to patients who have gynecologic tumors, desmoid tumors, hormone receptor-positive (HR+) breast cancer, and other HR+ solid tumors. This paper was chosen as the cover paper of Oncotarget’s Volume 12, Issue #4.

“Z-endoxifen administration was anticipated to bypass these variations, increasing active drug levels and potentially benefiting patients responding sub-optimally to tamoxifen.”

The Study

In a recent clinical trial (previous to this study), Z-endoxifen was well-tolerated when administered to women with breast cancer at doses up to 160 milligrams per day. In the current study, researchers investigated the drug movement, safety, and efficacy of Z-endoxifen administered in doses up to 360 milligrams per day in patients with predominantly non-breast malignancies—31 of 40 patients had malignancies other than breast cancer.

Between 2011 and 2017, 40 patients over the age of 18, with a life-expectancy of less than three months and treatment-refractory gynecologic malignancies, desmoid tumors, or hormone receptor-positive solid tumors, were administered daily oral doses of Z-endoxifen with a 3+3 dose escalation format over 8 dose levels in 28-day cycles. Drug safety, movement within the body, the effects and mechanisms affected, and clinical patient outcomes were evaluated by the researchers.

Patient urine and platelet concentrations of Z- and E-endoxifen were regularly measured using a validated, post-column fluorescence derivatization HPLC assay. 18F-FES, a substance that binds to estrogen receptors, uptake was measured by positron emission tomography (PET) imaging. Eye exams and computed tomography (CT) imaging were also used to monitor safety and efficacy.

“The trial was conducted under a National Cancer Institute (NCI)-sponsored IND with institutional review board approval at the NIH Clinical Center; informed written consent was obtained from all participants.”

Results & Conclusion

“Oral administration of Z-endoxifen in this study produced plasma levels well above those achieved with therapeutic doses of tamoxifen [26].”

Researchers in this trial found that Z-endoxifen can achieve improved plasma concentrations over tamoxifen, and Z-endoxifen may particularly benefit patients who have experienced disease progression on tamoxifen treatments. They also found that Z-endoxifen displays antitumorigenic properties, particularly in patients with desmoid tumors, and suggest that Z-endoxifen should be considered in patients with non-breast malignancies. 

“A notable finding in this study was the observation of antitumor activity in patients with prior progression on tamoxifen, including one with partial response and five with stable disease.”

Of the 40-patient cohort, 34 were evaluable and researchers reported that Z-endoxifen was generally well-tolerated in this study. While some adverse patient events were recorded in the trial, researchers deemed these results of patient diseases, and not caused by Z-endoxifen administration.

“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.”

Click here to read the full research study, published in Oncotarget.

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