Oncotarget publishes phase 1 study of Z-Endoxifen in patients with advanced cancers

Oncotarget published "Phase 1 study of Z-Endoxifen in patients with advanced gynecologic, desmoid, and hormone receptor-positive solid tumors" which reported that Z-endoxifen administration was anticipated to bypass these variations, increasing active drug levels, and potentially benefiting patients responding sub-optimally to tamoxifen.

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.

Three patients had partial responses and 8 had prolonged stable disease; 44.4% 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.

The Oncotarget article provides evidence that 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.

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 receptor-positive (PR+) breast cancer, and for chemoprevention in women at high risk of developing breast cancer."

Dr. Alice P. Chen, The Division of Cancer Treatment and Diagnosis, The National Cancer Institute in Bethesda Maryland

However, only about 50% of women with metastatic ER breast cancer who receive treatment with tamoxifen derive benefit, and trials have yielded mixed results regarding the clinical benefit of tamoxifen based on dose or serum concentration.

Endoxifen and 4-hydroxy-tamoxifen have similar binding affinities for ERα and ERβ, which are approximately 100-fold higher than those of tamoxifen or NDM-tamoxifen, but endoxifen plasma concentrations following tamoxifen administration are 5- to 20-fold higher than 4-hydroxy-tamoxifen.

Multiple other factors, including age, body mass index, gender, and polypharmacy contribute to how patients metabolize tamoxifen into endoxifen.

Among patients who receive tamoxifen, levels of endoxifen are lower in poor metabolizers, a finding that appears to correlate with significantly reduced time to tumor recurrence in these patients compared to those with greater CYP2D6 metabolism following treatment with adjuvant tamoxifen.

The Chen Research Team concluded in their Oncotarget Research Output that additional preclinical and clinical data demonstrate that Z-endoxifen can elicit major responses in ER breast cancer that has progressed on tamoxifen.

Despite these data in breast cancer, the optimal dose or concentration of Z-endoxifen in other tumors is unknown; however, our observation that high dose Z-endoxifen elicits antitumor activity in patients with non-breast malignancies would be in keeping with the data already observed demonstrating Z-endoxifen antitumor activity in breast cancers that have progressed on tamoxifen.

Furthermore, the overall safety profile, achievable plasma concentrations of Z-endoxifen, and clinical efficacy seen in this trial indicate that this agent may particularly benefit patients who have progressed on tamoxifen treatment and suggest that further studies of Z-endoxifen should be considered in patients with non-breast malignancies.

Source:
Journal reference:

Takebe, N., et al. (2021) Phase 1 study of Z-endoxifen in patients with advanced gynecologic, desmoid, and hormone receptor-positive solid tumors. Oncotarget. doi.org/10.18632/oncotarget.27887.

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