Endoxifen for Estrogen Receptor-Positive Breast Cancer

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

62 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug Z-Endoxifen Hydrochloride for estrogen receptor-positive breast cancer?

Research shows that Z-endoxifen, a potent form of tamoxifen, has demonstrated promising antitumor activity in patients with endocrine-resistant estrogen receptor-positive breast cancer, suggesting it may be effective where other treatments have failed. ^{1 2 3 4 5}

Is endoxifen safe for humans?

Endoxifen has been shown to be safe and well-tolerated in humans, with studies indicating that single oral doses are safe and have good bioavailability, meaning the body can effectively use the drug. ^{1 2 3 6 7}

How is the drug Z-Endoxifen Hydrochloride different from other treatments for estrogen receptor-positive breast cancer?

Z-Endoxifen Hydrochloride is a more potent form of tamoxifen, a common breast cancer drug, and it works even in cases where other treatments fail. Unlike tamoxifen, it doesn't rely on the body's ability to metabolize it, which can vary among patients, and it has fewer side effects on the uterus. ^{1 2 5 8 9}

What is the purpose of this trial?

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 cancer that has spread to other places in the body (metastatic) or has come back at or near the same place as the original tumor (locally recurrent). Estrogen can cause the growth of breast cancer cells. Hormone therapy using Z-endoxifen hydrochloride may fight breast cancer by blocking the use of estrogen by tumor cells.

Research Team

Matthew P. Goetz

Principal Investigator

Mayo Clinic

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

References

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

Endoxifen, an Estrogen Receptor Targeted Therapy: From Bench to Bedside. [2022]

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

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

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

Fast and Adequate Liquid Chromatography-Tandem Mass Spectrometric Determination of Z-endoxifen Serum Levels for Therapeutic Drug Monitoring. [2017]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Evaluating Elacestrant in the Management of ER-Positive, HER2-Negative Advanced Breast Cancer: Evidence to Date. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Antitumor activity of Z-endoxifen in aromatase inhibitor-sensitive and aromatase inhibitor-resistant estrogen receptor-positive breast cancer. [2022]

6. United States 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. [2023]

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

Endoxifen, a new cornerstone of breast cancer therapy: demonstration of safety, tolerability, and systemic bioavailability in healthy human subjects. [2017]

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

Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: preliminary results of the Italian Tamoxifen Anastrozole Trial. [2022]

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

Endometrial tubal metaplasia in a young puerperal woman after breast cancer. [2018]