Tamoxifen vs Endoxifen for Advanced Breast Cancer

Not currently recruiting at 670 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Aromatase inhibitors

Must not be taking: CYP2D6 inhibitors

Disqualifiers: Brain metastases, Uncontrolled hypertension, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 21 days per cycle, ongoing until disease progression or unacceptable toxicity

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two hormone therapies, tamoxifen citrate and z-endoxifen hydrochloride, to determine which better treats advanced breast cancer that has spread and is fueled by estrogen. Both treatments aim to combat cancer by lowering estrogen levels in the body, potentially slowing or stopping tumor growth. Women with estrogen receptor-positive (cancer feeds on estrogen) and HER2-negative (lacks a specific growth-promoting protein) breast cancer, who have previously received certain hormone therapies, may be suitable candidates. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot be on strong inhibitors of CYP2D6 or other investigational agents. You also need to stop any chemotherapy, immunotherapy, biologic therapy, hormonal therapy, monoclonal antibodies, radiation therapy, or targeted therapy at least 2 weeks before starting the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that both tamoxifen citrate and z-endoxifen hydrochloride have undergone safety testing in people.

Tamoxifen citrate, a well-researched drug, has been used for a long time. Data from 20 studies over many years indicate that tamoxifen can reduce the risk of dying from breast cancer by one-third over 15 years. It is generally well-tolerated, with a well-known safety record based on extensive research.

Z-endoxifen hydrochloride is newer and not as thoroughly studied as tamoxifen. Early research shows that patients could continue using z-endoxifen for several treatment cycles, suggesting it might be well-tolerated, although more long-term safety data is needed. The FDA has shown positive interest in its development, indicating confidence in its early safety results.

Both treatments have demonstrated safety in people, but tamoxifen has more long-term data to support its safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Endoxifen for advanced breast cancer because it offers a new approach compared to traditional treatments like Tamoxifen. Unlike Tamoxifen, which needs to be metabolized in the body to become active, Endoxifen is already in its active form, potentially leading to more consistent and effective results. This could mean better outcomes and fewer side effects for patients, as the drug doesn't rely on the body's metabolic processes to work effectively. Additionally, Endoxifen's unique formulation might provide a new option for patients who don't respond well to Tamoxifen, offering hope for improved management of advanced breast cancer.

What evidence suggests that this trial's treatments could be effective for advanced breast cancer?

This trial will compare tamoxifen citrate and z-endoxifen hydrochloride for advanced breast cancer. Studies have shown that tamoxifen citrate effectively treats a type of breast cancer that relies on estrogen to grow, reducing the risk of recurrence by 40% and lowering the chance of death by about 30%. Research suggests that z-endoxifen hydrochloride, which participants in this trial may receive, may stop cancer cells from using estrogen and potentially offer better bone protection than tamoxifen. Both treatments target the hormones that help cancer grow, but their comparative effectiveness is still under investigation in this trial. ^{1 2 3 4 6}

Who Is on the Research Team?

Matthew P Goetz

Principal Investigator

Alliance for Clinical Trials in Oncology

Are You a Good Fit for This Trial?

This trial is for postmenopausal women with advanced or metastatic estrogen receptor-positive, HER2-negative breast cancer. Participants must have been treated previously with an aromatase inhibitor and can't be on strong CYP2D6 inhibitors or have had more than two chemotherapy treatments in the metastatic setting. They should not have brain metastases, uncontrolled illnesses, certain blood disorders, or a recent history of significant blood clots.

Inclusion Criteria

Your total bilirubin level is not more than 1.5 times the upper limit of normal.

You do not have any of the listed other health problems.

I was treated with an aromatase inhibitor for my cancer and it did not respond well.

Exclusion Criteria

I am not postmenopausal.

Your creatinine levels are higher than 1.5 times the normal range.

Your AST levels are higher than the normal range, especially if you have cancer that has spread to your liver.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either z-endoxifen hydrochloride or tamoxifen citrate orally on days 1-21, with courses repeating every 21 days in the absence of disease progression or unacceptable toxicity.

21 days per cycle, ongoing until disease progression or unacceptable toxicity

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up occurring yearly for up to 5 years.

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Endoxifen Hydrochloride
• Tamoxifen Citrate

Trial Overview The study compares tamoxifen citrate and z-endoxifen hydrochloride to see which one is better at treating patients whose breast cancer has spread and relies on estrogen to grow. The trial includes lab biomarker analysis and pharmacological studies to assess how well these hormone therapies work.

How Is the Trial Designed?

Group I: Arm II (tamoxifen citrate) Experimental Treatment 3 Interventions

Patients receive tamoxifen citrate PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression and bone metastases may cross over to Arm I and receive z-endoxifen hydrochloride starting no later than 28 days after documentation of disease progression.

Group II: Arm I (z-endoxifen hydrochloride) Experimental Treatment 3 Interventions

Patients receive z-endoxifen hydrochloride PO on days 1-21. Courses repeat every 21 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

Tamoxifen is widely used by 7 million women for breast cancer treatment and has been shown to significantly improve patient survival with minimal adverse effects.

While there is a slightly increased risk of endometrial cancer at the 20 mg/d dosage, this risk is considered minimal, and routine monitoring primarily involves clinical examinations rather than systematic endometrial testing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Monitoring women on tamoxifen ]. Lansac, J., Diouf, A.[2013]

Tamoxifen citrate has been a crucial treatment for breast cancer over the past 25 years, significantly improving survival rates and reducing the risk of developing cancer in the other breast.

Patients appreciate the additional benefits of tamoxifen on cholesterol levels and bone health, but they also express concerns about potential side effects affecting their daily lives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tamoxifen's impact on the management of breast cancer: patient perspectives. Reichman, BS.[2013]

Only 27.4% of surveyed primary care physicians prescribed tamoxifen for breast cancer prevention in the past year, indicating that its use is not widespread among these doctors.

Factors influencing the decision to prescribe tamoxifen included personal connections to breast cancer, patient inquiries about the drug, and the belief that its benefits outweigh the risks, while concerns about endometrial cancer risk had less impact on prescribing decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prescription of tamoxifen for breast cancer prevention by primary care physicians. Armstrong, K., Quistberg, DA., Micco, E., et al.[2015]

Aromatase inhibitors, such as anastrozole and letrozole, show superior efficacy and a better safety profile compared to tamoxifen for treating metastatic breast cancer, making them a preferred option in first- and second-line treatments.

The ATAC trial indicates that anastrozole not only improves disease-free survival in hormone receptor-positive patients but also reduces the risk of developing contralateral breast cancer, highlighting its effectiveness in postmenopausal women.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aromatase inhibitors in breast cancer: an update. Lake, DE., Hudis, C.[2018]

New endocrine therapies, such as aromatase inhibitors (anastrozole, letrozole, exemestane) and fulvestrant, show superior efficacy and tolerability compared to the traditional treatment tamoxifen for postmenopausal women with advanced breast cancer.

Sequential use of these newer agents can prolong the effectiveness of endocrine therapies while minimizing the acute toxicities associated with cytotoxic chemotherapy, making them a valuable option in palliative care for advanced breast cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tamoxifen--what next? Gradishar, WJ.[2019]

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]

Fulvestrant is a new steroidal estrogen receptor antagonist that effectively downregulates estrogen and progesterone receptors, showing promise as a treatment option for postmenopausal women with advanced breast cancer, especially in cases resistant to tamoxifen and aromatase inhibitors.

Compared to traditional therapies like tamoxifen and selective estrogen receptor modulators, fulvestrant offers a unique mechanism of action with no agonist activity, highlighting its potential role in the sequencing of endocrine therapies for better management of breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endocrine treatment options for advanced breast cancer--the role of fulvestrant. Robertson, JF., Come, SE., Jones, SE., et al.[2018]

Citations

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

Phase 1 study of Z-endoxifen in patients with advanced ... However, only about 50% of women with metastatic ER+ breast cancer who receive treatment with tamoxifen derive benefit, and trials have yielded ...

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

Study Details | NCT01327781 | Z-Endoxifen Hydrochloride ... Hormone therapy using Z-endoxifen hydrochloride may fight breast cancer by blocking the use of estrogen by tumor cells. Detailed Description. PRIMARY OBJECTIVES ...

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

Advancing Metastatic Breast Cancer Treatment: Z- ... Beyond its SERM activity, it also targets PKCβ1 and has shown comparable or superior bone-protective effects when compared to tamoxifen ( ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7864591/

The Development of Endoxifen for Breast Cancer - PMC It was developed as a treatment for women with estrogen receptor–positive breast cancer, with the idea that blocking this receptor could promote anticancer ...

5. 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 ...

6. aacrjournals.org aacrjournals.org/cancerres/article/85/8_Supplement_2/CT257/761741/Abstract-CT257-SMART-2-0-Interval-breast-cancer

Abstract CT257: SMART 2.0 Interval breast cancer reduction ... The aim of SMART2.0 is to evaluate whether low-dose Endoxifen can reduce the incidence of breast cancer in high-risk women compared to placebo.