Endoxifen for Hormone-Receptor-Positive Cancer

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Steroids, Anti-seizure medications

Disqualifiers: Brain metastases, Uncontrolled diabetes, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 28 days per cycle

40 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: * Some types of cancer cells that have hormone receptors on their surfaces need the hormone estrogen to grow. The drug tamoxifen blocks estrogen from binding to the tumor cells, which helps to slow or stop the growth of cancer. Tamoxifen has been approved for treatment of certain types of estrogen-linked cancers, such as breast and ovarian cancer. * The experimental drug Z-Endoxifen HCl (endoxifen) is related to tamoxifen, and has been shown to work against similar estrogen-linked cancers. In many cancer patients, tamoxifen is turned into endoxifen by enzymes in the liver; however, not all people have the liver enzymes that can turn tamoxifen into endoxifen, which means that the drug cannot work properly. Taking certain other drugs at the same time as tamoxifen can also keep it from turning into endoxifen. Researchers are interested in determining whether endoxifen tablets are effective in slowing or stopping tumor growth in individuals whose hormone-linked tumors have not responded to standard treatment. Objectives: - To test the safety and effectiveness of daily endoxifen in individuals with hormone receptor positive solid tumors that have not responded to standard treatment. Eligibility: - Individuals at least 18 years of age who have been diagnosed with hormone receptor positive solid tumors (breast or other tumors), desmoid tumors, or gynecologic tumors that have not responded to standard treatment. Individuals with breast cancer must have had at least one prior chemotherapy regimen and one prior hormonal regimen for metastatic disease. Design: * Participants will be screened with a full medical history (including prior hormone use) and physical examination, as well as blood and urine tests, tumor imaging studies, and an eye examination. * Participants will take endoxifen tablets daily for 28-day cycles of treatment, and will be asked to keep a medication diary to record any side effects. * Participants will have regular clinic visits with blood and urine samples and imaging studies to evaluate the cancer's response to treatment. * Participants will continue to take endoxifen for as long as the cancer responds to the treatment.

Will I have to stop taking my current medications?

The trial requires that you have not had hormonal therapy, chemotherapy, or biologic therapy within 4 weeks before starting the study (6 weeks for certain drugs). However, you can continue taking bisphosphonates or therapeutic anticoagulation medications.

What data supports the effectiveness of the drug Endoxifen for hormone-receptor-positive cancer?

Research shows that Z-endoxifen, a form of Endoxifen, has strong antitumor effects in breast cancer that is resistant to other hormone treatments. It is more potent than tamoxifen, a commonly used breast cancer drug, and has shown promising results in clinical studies for various hormone-receptor-positive cancers. ^{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 Endoxifen different from other treatments for hormone-receptor-positive cancer?

Endoxifen is a more potent form of tamoxifen, a common breast cancer drug, and it works independently of the CYP2D6 enzyme, which can vary in effectiveness among patients. This makes Endoxifen potentially more effective for those who do not respond well to tamoxifen due to genetic differences in metabolizing the drug. ^{1 3 4 5 7}

Research Team

Alice P Chen, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults over 18 with hormone receptor positive solid tumors, including breast and gynecologic cancers, that haven't improved with standard treatments. Participants must have tried at least one chemotherapy and hormonal regimen if they have breast cancer. They should not be on certain medications or have had recent major surgery, and their organ function needs to meet specific criteria.

Inclusion Criteria

I have a cancer that started in my reproductive organs.

My tumor is positive for estrogen or progesterone receptors.

I have breast cancer and have been treated with tamoxifen or aromatase inhibitors.

Exclusion Criteria

Patients with clinically significant illnesses that could compromise participation in the study

I have cancer spread to my spine or near vital organs that hasn't been treated.

Patients receiving any other investigational agents

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants take endoxifen tablets daily for 28-day cycles and keep a medication diary to record any side effects

28 days per cycle

Regular clinic visits with blood and urine samples and imaging studies

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

Optional Imaging

Optional FES PET/CT scans to evaluate tumor estrogen receptor activity

During week 1 of cycle 1

Treatment Details

Interventions

• Endoxifen

Trial Overview The trial is testing the safety and effectiveness of a drug called Z-Endoxifen in tablet form for patients whose tumors are still growing despite previous treatments. The study involves taking the medication daily in cycles, monitoring side effects through regular clinic visits, blood tests, imaging studies, and an eye exam.

Participant Groups

Group I: 1 Experimental Treatment 1 Intervention

Z-endoxifen will be administered orally once a day in 28-day cycles

Endoxifen is already approved in India for the following indications:

Approved in India as Endoxifen for:

• Bipolar I disorder

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

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]

(Z)-Endoxifen is a more potent selective estrogen receptor modulator than tamoxifen, showing significant tumor growth inhibition in a preclinical model with female athymic mice at doses of 4-8 mg/kg.

The study confirmed the active configuration of (Z)-endoxifen and developed a validated HPLC method for quality control, ensuring accurate quantitation and impurity profiling, which is crucial for its therapeutic evaluation in ER+ breast cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of the isomeric configuration and impurities of (Z)-endoxifen by 2D NMR, high resolution LC⬜MS, and quantitative HPLC analysis. Elkins, P., Coleman, D., Burgess, J., et al.[2021]

References

1. 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]

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

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

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

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

4. England pubmed.ncbi.nlm.nih.gov

Characterization of the isomeric configuration and impurities of (Z)-endoxifen by 2D NMR, high resolution LC⬜MS, and quantitative HPLC analysis. [2021]

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

A convenient synthesis of (Z)-4-hydroxy-N-desmethyltamoxifen (endoxifen). [2017]

6. 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]

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

Increasing tamoxifen dose in breast cancer patients based on CYP2D6 genotypes and endoxifen levels: effect on active metabolite isomers and the antiestrogenic activity score. [2017]