Tamoxifen vs Endoxifen for Advanced Breast Cancer

Recruiting at 655 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

81 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This randomized phase II trial studies how well tamoxifen citrate works compared with z-endoxifen hydrochloride in treating patients with breast cancer that has spread to nearby tissue or lymph nodes or other parts of the body and has estrogen receptors but not human epidermal growth factor receptor 2 (HER2) receptors on the surface of its cells. Estrogen can cause the growth of tumor cells. Hormone therapy using tamoxifen citrate or z-endoxifen hydrochloride may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known whether tamoxifen citrate or z-endoxifen hydrochloride is more effective in treating patients with breast cancer.

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 Tamoxifen and Endoxifen safe for humans?

Tamoxifen has been used by millions of women for breast cancer and is generally considered safe, with few serious side effects. However, there is a slightly increased risk of endometrial cancer and some concerns about tolerability. Endoxifen, a metabolite of Tamoxifen, has been evaluated in early studies, but more research is needed to fully understand its safety profile. ^{1 2 3 4 5}

How does the drug Endoxifen differ from other treatments for advanced breast cancer?

Endoxifen is a metabolite of tamoxifen, and its use in advanced breast cancer is being explored as it may offer benefits in cases where tamoxifen resistance has developed. Unlike tamoxifen, which is a selective estrogen receptor modulator (SERM), Endoxifen directly targets the estrogen receptor, potentially providing a more effective option for patients who do not respond to traditional therapies. ^{6 7 8 9 10}

What data supports the effectiveness of the drug Endoxifen Hydrochloride and Tamoxifen Citrate for advanced breast cancer?

Tamoxifen has been widely used and is effective in treating breast cancer, both in early and advanced stages. Endoxifen, a more potent form of tamoxifen, has shown promise in early studies, but more research is needed to fully understand its role in treatment. ^{4 6 8 10 11}

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

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

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

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

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]

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]

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]

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]

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]

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]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

Aromatase inhibitors in breast cancer: an update. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Endocrine treatment options for advanced breast cancer--the role of fulvestrant. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Prescription of tamoxifen for breast cancer prevention by primary care physicians. [2015]

5. Netherlands pubmed.ncbi.nlm.nih.gov

The development of tamoxifen for breast cancer therapy: a tribute to the late Arthur L. Walpole. [2020]

6. France pubmed.ncbi.nlm.nih.gov

[Monitoring women on tamoxifen ]. [2013]

7. United States pubmed.ncbi.nlm.nih.gov

Shifting paradigms in hormonal therapy for breast cancer. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Tamoxifen--what next? [2019]

9. United States pubmed.ncbi.nlm.nih.gov

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

10. England pubmed.ncbi.nlm.nih.gov

Fulvestrant ('Faslodex')--a new treatment option for patients progressing on prior endocrine therapy. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Recent advances in breast cancer (the Twenty-fourth San Antonio Breast Cancer Symposium, December, 2001). [2019]