Derivative of Tamoxifen Demonstrates Prolonged Anticancer Benefit in Early Stage Trial

Z-endoxifen demonstrated promising anti-tumor activity in a stage 1 clinical trial of patients with endocrine-refractory, estrogen receptor-positive metastatic breast cancer.

The findings from the first-in-human trial, published in the Journal of Clinical Oncology, showed treatment with Z-endoxifen was safe and resulted in effective tumor shrinkage in women whose tumors had progressed on standard treatments, including tamoxifen.

“Tamoxifen, is converted into endoxifen in the liver by an enzyme called CYP2D6,” said lead author Matthew Goetz, MD. “Our previous research found that tamoxifen may be less effective in women with poor CYP2D6 metabolism.”

For the study, investigators sought to determine oral Z-endoxifen toxicities, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity.

Of 41 patients enrolled in the study, 38 were evaluable for MTD determination. Endocrine regimens in which progression occurred included aromatase inhibitor, fulvestrant, and tamoxifen.

Participants received endoxifen once daily at 7 dose levels ranging from 20-mg to 160-mg, with dose escalation stopping at 160-mg per day given lack of MTD and endoxifen concentrations greater than 1900 ng/mL.

The results of the study showed endoxifen clearance was unaffected by CYP2D6 metabolism, provided acceptable toxicity, and demonstrated promising anti-tumor activity.

“The primary goal of the study was to safely deliver therapeutic levels of endoxifen without the requirement for CYP2D6 liver metabolism,” Dr Goetz said. “However, one of the most surprising observations was the prolonged anticancer benefit, [which] in some cases lasted more than 2 years in women who had progressed on standard anti-estrogen therapies.”

Data from the recently completed randomized trial comparing tamoxifen with Z-endoxifen are expected in 2018.

“We are encouraged by these results and [are] hopeful that, based on these data and ongoing studies, Z-endoxifen could become a new US Food and Drug Administration-approved treatment for women with estrogen positive metastatic breast cancer,” Dr Goetz said.