Zonalta (Z-endoxifen hydrochloride)

P1, N=62, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Oct 2025

P3, N=490, Recruiting, Jina Pharmaceuticals Inc.

P3, N=124, Completed, Jina Pharmaceuticals Inc. | Recruiting --> Completed

P1, N=40, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2024 --> Jun 2026

P2, N=81, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2024 --> Feb 2025

We formulated the tamoxifen metabolite (E/Z)-endoxifen for transdermal delivery and tested it in a placebo-controlled, double-blinded Phase I trial with dose escalation from 10 to 20 mg daily. At the endoxifen doses and duration used, and the tissue concentration achieved, we observed a non-significant overall reduction of tumor proliferation (Ki67 LI) and significant downregulation of gene signatures known to promote cancer invasion (FN1, SERPINH1, PLOD2, PDGFA, ITGAV) (p = 0.03). Transdermal endoxifen is an important potential breast cancer prevention agent but formulations with better dermal penetration are needed.

P2b; The median 4-hydroxytamoxifen concentrations deep in the breast were nonsignificantly higher in the oral tamoxifen group (5.7 [IQR, 4.0-7.9] vs 3.8 [IQR, 1.3-7.9] ng/g), whereas endoxifen was abundant in the oral tamoxifen group and minimal in the 4-hydroxytamoxifen gel group (median, 13.0 [IQR, 8.9-20.6] vs 0.3 [IQR, 0-0.3] ng/g; P < .001). New transdermal approaches must deliver higher drug quantities and/or include the most potent metabolites. ClinicalTrials.gov Identifier: NCT02993159.

P2, N=81, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2023 --> May 2024

P1, N=40, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2023 --> Jun 2024

P2, N=81, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2022 --> May 2023

P1, N=40, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2022 --> Jun 2023

P1, N=40, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2021 --> Jun 2022

P2, N=81, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Jan 2022 --> Nov 2020

P2, N=80, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Jan 2021 --> Jan 2022

In this retrospective analysis of 406 estrogen receptor positive breast cancer patients receiving adjuvant tamoxifen as initial treatment, we have associated our previously reported thresholds for the two active metabolites, Z-endoxifen and Z-4OHtam, with treatment outcomes in an independent cohort of breast cancer patients. This is the first study to confirm the association between a published active tamoxifen metabolite threshold and breast cancer outcome in an independent patient cohort. Pre-menopausal patients receiving 5-year of tamoxifen alone may benefit from therapeutic drug monitoring to ensure tamoxifen effectiveness.

P1, N=40, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Jun 2021 --> Jun 2020

In endocrine-sensitive and letrozole-resistant breast tumors, Z-endoxifen results in robust antitumor and antiestrogenic activity compared to tamoxifen and aromatase inhibitor monotherapy. These data support the ongoing development of Z-endoxifen.

The two active metabolitesZ-4-hydroxy-tamoxifen and Z-endoxifen, could not be quantified in milk the first days after tamoxifen intake, but increased over time and reached clinically significant levels after day 18.ConclusionThis study demonstrates for the first time in human that tamoxifen and its metabolites transfer into milk. Since tamoxifen has a complete oral bioavailability, a long half-life (>7 days) and may interfere with the normal development of the infant, mothers should not breastfeed during tamoxifen treatment.

In patients with CYP2D6-variant alleles, increasing tamoxifen dosing did not achieve a higher PFS rate at 6 months. The CYP2D6 genotype solely cannot explain individual variability in the efficacy of tamoxifen.

In previous studies, steady-state Z-endoxifen plasma concentrations (ENDOss) correlated with relapse-free survival in women on tamoxifen (TAM) treatment for breast cancer. Multivariable regression analysis selected log(DM/DX) as the best predictor, with patients' age, weak inhibitor use, and CYP2D6 phenotype decreasingly important: log-ENDOss = 0.162 - log(DM/DX) × 0.170 + age × 0.0063 - weak inhibitor use × 0.250 + IM × 0.105 + (NM + UM) × 0.210; (R  = 0.51). In conclusion, log(DM/DX) seems superior to genotype-derived CYP2D6 phenotype in predicting ENDOss.