Endoxifen for Estrogen Receptor-Positive Breast Cancer

Not currently recruiting at 2 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must be taking: Hormone therapy

Must not be taking: Anti-coagulants, Bisphosphonates

Disqualifiers: Stroke, Seizures, DVT, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of Z-endoxifen hydrochloride in treating estrogen receptor-positive (ER+) breast cancer that has spread or recurred. The main goal is to determine the optimal dose and understand its side effects. The treatment blocks estrogen, potentially slowing or stopping cancer cell growth. Women with metastatic or locally recurrent ER+ breast cancer who have not responded to other treatments might be suitable candidates for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

Will I have to stop taking my current medications?

The trial requires that you stop taking chemotherapy, immunotherapy, biologic therapy, hormonal therapy, monoclonal antibodies, radiation therapy, and anti-Her-2 directed therapy at least 3 weeks before joining. If you are on anti-coagulant therapy for maintenance, you may be eligible if your condition was stable for over 12 months.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that Z-endoxifen is generally safe for people. Studies involving over 700 patients have found that Z-endoxifen is well tolerated. No reports have indicated a dose causing severe side effects, meaning people have taken it without reaching a harmful level.

In another study, a single oral dose of Z-endoxifen, between 0.5 mg and 4 mg, proved safe, with no major side effects reported. Additionally, research in women with breast cancer demonstrated that the treatment was not only safe but also helped shrink tumors.

Overall, these findings suggest that Z-endoxifen is a promising and safe option for treating breast cancer, with minimal side effects observed in these studies. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for estrogen receptor-positive breast cancer, like tamoxifen, work by blocking estrogen from binding to its receptor. But Z-endoxifen hydrochloride works differently, as it is an active metabolite of tamoxifen that doesn't require conversion in the body. This means it could be more effective for patients who struggle to metabolize tamoxifen efficiently. Researchers are excited because this approach may offer a more direct and potentially more effective treatment option with fewer complications related to drug metabolism.

What evidence suggests that Z-endoxifen hydrochloride might be an effective treatment for estrogen receptor-positive breast cancer?

Research has shown that Z-endoxifen hydrochloride can help treat estrogen receptor-positive (ER+) breast cancer by blocking estrogen, which may stop cancer cell growth. Studies involving over 700 patients indicate that Z-endoxifen is generally well-tolerated and effective for patients whose cancer has continued to grow despite other treatments. It has proven to be a strong treatment option for various stages of breast cancer. Early results suggest it is safe, as trials have not identified a maximum safe dose. ^{1 2 3 6 7}

Who Is on the Research Team?

Matthew P. Goetz

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

This trial is for postmenopausal women with ER+ metastatic or locally recurrent breast cancer. Participants must have had prior hormone therapy, be able to swallow capsules, and have a life expectancy over 16 weeks. They should not have uncontrolled brain metastases, recent seizures, active blood clots, or other severe diseases that could interfere with the study.

Inclusion Criteria

I understand the study's risks and benefits and can give written consent.

I have had hormone therapy for cancer that has spread, using tamoxifen or an aromatase inhibitor.

Your platelet count is at least 75,000 per microliter of blood.

Exclusion Criteria

I started hormonal therapy less than 3 weeks ago.

I have not had any HER2-targeted therapy in the last 3 weeks.

I haven't received monoclonal antibodies in the last 3 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Z-endoxifen hydrochloride orally on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

3 months

What Are the Treatments Tested in This Trial?

Interventions

• Z-Endoxifen Hydrochloride

Trial Overview The trial is testing Z-endoxifen hydrochloride's safety and optimal dosage in patients whose breast cancer grows in response to estrogen. It includes lab biomarker analysis and pharmacological studies along with questionnaires about patient experiences.

How Is the Trial Designed?

Group I: Treatment (Z-endoxifen hydrochloride) Experimental Treatment 4 Interventions

Patients receive Z-endoxifen hydrochloride PO on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Endoxifen, a potent metabolite of tamoxifen, shows promise as an alternative therapy in breast cancer, but current research primarily focuses on its use in metastatic cases, indicating a need for further studies to establish its therapeutic role.

Pharmacogenetic factors, particularly CYP2D6 genotypes, significantly impact tamoxifen metabolism and clinical outcomes, suggesting that personalized treatment approaches based on genetic testing may be necessary, although evidence for monitoring endoxifen concentrations is still limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen. Sanchez-Spitman, AB., Swen, JJ., Dezentje, VO., et al.[2019]

In a study of 3,046 postmenopausal women with ductal carcinoma in situ, 28.5% discontinued treatment with anastrozole or tamoxifen, with specific adverse events like thrombosis and arthralgia linked to discontinuation of both drugs.

Patient-reported outcomes (PROs) such as pain interference and hot flashes were significant factors in discontinuing tamoxifen, while only hot flashes were associated with discontinuation of anastrozole, highlighting the importance of both adverse events and patient experiences in treatment adherence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity Index, Patient-Reported Outcomes, and Early Discontinuation of Endocrine Therapy for Breast Cancer Risk Reduction in NRG Oncology/NSABP B-35. Henry, NL., Kim, S., Hays, RD., et al.[2023]

A new high-performance liquid chromatography-tandem mass spectrometry assay has been developed and validated to accurately measure endoxifen levels in serum, which is crucial for personalized tamoxifen therapy in breast cancer patients.

In a study of over 500 patients, 32.7% had endoxifen levels below the therapeutic threshold of 5.9 ng/mL, indicating a significant number of patients may be at risk for breast cancer recurrence due to subtherapeutic drug levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fast and Adequate Liquid Chromatography-Tandem Mass Spectrometric Determination of Z-endoxifen Serum Levels for Therapeutic Drug Monitoring. de Krou, S., Rosing, H., Nuijen, B., et al.[2017]

Z-endoxifen demonstrated superior antitumor activity compared to tamoxifen and letrozole in both endocrine-sensitive and letrozole-resistant breast cancer models, significantly reducing tumor volumes in treated mice.

In letrozole-resistant tumors, Z-endoxifen not only outperformed tamoxifen and letrozole but also showed comparable efficacy to combination therapies like exemestane plus everolimus and fulvestrant, indicating its potential as a robust treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of Z-endoxifen in aromatase inhibitor-sensitive and aromatase inhibitor-resistant estrogen receptor-positive breast cancer. Jayaraman, S., Hou, X., Kuffel, MJ., et al.[2022]

Z-endoxifen, a potent metabolite of tamoxifen, shows promising antitumor activity in patients with various cancers, including endocrine-refractory metastatic breast cancer, and has substantial oral bioavailability.

Unlike tamoxifen, Z-endoxifen appears to have beneficial effects on bone health while causing little to no endometrial proliferation, making it a potentially safer alternative for breast cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endoxifen, an Estrogen Receptor Targeted Therapy: From Bench to Bedside. Jayaraman, S., Reid, JM., Hawse, JR., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7899551/

Phase 1 study of Z-endoxifen in patients with advanced ... Additional preclinical and clinical data demonstrate that Z-endoxifen can elicit major responses in ER+ breast cancer that has progressed on ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT01327781

Study Details | NCT01327781 | Z-Endoxifen Hydrochloride ... This phase I trial studies the side effects and the best dose of Z-endoxifen hydrochloride in treating patients with estrogen receptor-positive (ER+) breast ...

3. investors.atossatherapeutics.com investors.atossatherapeutics.com/2025-07-29-Atossa-Therapeutics-Announces-Positive-FDA-Feedback,-Advances-Toward-IND-for-Z-Endoxifen-Clinical-Program-in-ER-HER2-Metastatic-Breast-Cancer

Atossa Therapeutics Announces Positive FDA Feedback ... The company's lead product candidate, (Z)-endoxifen, is a highly potent SERM designed for use across the breast cancer spectrum, including ...

4. targetedonc.com targetedonc.com/view/advancing-metastatic-breast-cancer-treatment-z-endoxifen-nears-ind-submission

Advancing Metastatic Breast Cancer Treatment: Z- ... To date, clinical studies involving over 700 patients have demonstrated that Z-endoxifen is well tolerated, with no maximum tolerated dose ...

5. clinicaltrial.be clinicaltrial.be/en/details/76987?active_not_recruiting=1&completed=0&enrolling_by_invitation=1&only_active=0&only_eligible=0&only_recruiting=0&per_page=20

Z-Endoxifen Hydrochloride in Treating Patients With Metas... To determine the frequency of estrogen receptor 1 (ESR1) mutations and the presence of antitumor activity (response rate and progression free ...

6. ascopubs.org ascopubs.org/doi/10.1200/jco.2010.28.15_suppl.3087

First-in-human study evaluating safety and ... Results: Single oral dose of endoxifen at 0.5, 1, 2, or 4 mg was safe and well tolerated. Adverse events were not found and no clinically ...

7. newsnetwork.mayoclinic.org newsnetwork.mayoclinic.org/discussion/science-saturday-z-endoxifen-emerges-as-potential-breast-cancer-treatment/

Z-Endoxifen emerges as potential breast cancer treatment Results of a phase I study in women showed that the treatment was safe and reduced tumors. Z-endoxifen, a potent derivative of the drug ...