Endoxifen for Hormone-Receptor-Positive Cancer

No longer 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug called endoxifen to determine if it can slow or stop the growth of cancers that rely on hormones like estrogen. It targets individuals whose hormone-linked tumors, such as certain types of breast, gynecologic, or desmoid tumors, have not responded well to standard treatments. Participants will take endoxifen tablets daily and attend regular check-ups to monitor the cancer's response. This trial may suit those with hormone receptor-positive solid tumors that haven't improved with other treatments. As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding how endoxifen works in people.

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.

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

Research has shown that endoxifen is generally safe and well-tolerated. In one study, different doses of endoxifen, ranging from 0.5 mg to 4 mg, were tested, and participants did not experience any serious side effects. Another study involving patients with various tumors also found that endoxifen was well-tolerated, with no major adverse events reported.

These results are encouraging, especially since endoxifen is related to tamoxifen, a drug safely used for years to treat estrogen-related cancers like breast cancer. This suggests that endoxifen might be similarly safe. However, it is important to remember that this trial is still in the early stages. Researchers are focusing on ensuring its safety for more people in the future. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard hormone therapies for hormone-receptor-positive cancer, Endoxifen offers a unique approach by using a metabolite of tamoxifen directly. Most treatments rely on the body's ability to convert tamoxifen into its active form, which can vary from person to person. Endoxifen bypasses this step, potentially offering a more consistent and effective treatment. Researchers are excited because this could lead to better outcomes and fewer side effects for patients.

What evidence suggests that endoxifen might be an effective treatment for hormone-receptor-positive cancer?

Research shows that endoxifen blocks estrogen in breast cancer cells, similar to tamoxifen, helping to slow or stop tumor growth. Studies have found that Z-endoxifen, a byproduct of tamoxifen, is effective against certain breast cancers unresponsive to hormones. Endoxifen's advantage lies in its ability to bypass liver processing, unlike tamoxifen, benefiting those who cannot convert tamoxifen properly. This direct method could make endoxifen a viable option for patients whose tumors have not responded to other treatments. Early results suggest it might be easier to tolerate while targeting estrogen in early-stage breast cancer. Participants in this trial will receive Z-endoxifen orally once a day in 28-day cycles. ^{1 3 6 7 8}

Who Is on the Research Team?

Alice P Chen, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

Citations

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Endoxifen (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxy-tamoxifen · Authors · Affiliation.

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Here, we describe modulation of the estrogen receptor (ER) liganded with antiestrogens (endoxifen and 4-hydroxytamoxifen) and an estrogenic triphenylethylene ( ...

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pmc.ncbi.nlm.nih.gov

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

The Development of Endoxifen for Breast Cancer - PMC

Therefore, endoxifen may be an effective but more tolerable approach to targeting the estrogen receptor in premenopausal women with early-stage breast cancer.

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

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Our current trial examined the safety and tolerability of Z-endoxifen in patients with gynecologic tumors, desmoid tumors, hormone receptor- ...

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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 ...

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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 ...