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Hormone Receptor-Positive BreastPhase 1NCT01273168

Endoxifen in Adults With Hormone Receptor Positive Solid Tumors

A Phase 1 study testing Z-Endoxifen in people with Hormone Receptor-Positive Breast and Gynecologic, run by National Cancer Institute (NCI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 to 120 years
What is being tested?
Z-Endoxifen
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
40 participants
Where
1 siteUnited States
Study dates
1 Mar 2011to 19 Dec 2025
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 120 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients with the following types of histologically documented solid tumors:
  • ER +/PR+, ER+/PR-, or ER-/PR+ breast cancer
  • Gynecologic tumors (endometrial, ovarian, uterine, fallopian tube, peritoneal, etc.)
  • Desmoid tumors
  • Tumors that are ER+ or PR+ by immunohistochemistry (including low-level expression) such as non-small cell lung, colorectal, and prostate
  • Patients with breast cancer must have had at least one prior chemotherapy regimen for metastatic disease. Additionally, patients with breast cancer must have received prior tamoxifen and/or aromatase inhibitor therapy (if postmenopausal) with at least one hormonal regimen in the metastatic setting. Patients with HER2+ breast cancer must have progressed after at least one prior HER2-directed regimen (trastuzumab, lapatinib) for metastatic disease.
Show all 22Show fewer
  • All other patients must have disease that has progressed following at least one line of standard therapy. Prior therapy with tamoxifen is allowed.
  • Patients enrolled based on tumor ER/PR status must have ER/PR status confirmed by the Laboratory of Pathology, NIH. ER/PR status will be determined on a metastatic site, if possible; otherwise, the original site or available tissue will be acceptable.
  • Patients must have recovered to at least eligibility levels following any display of adverse events and/or toxicity due to prior chemotherapy or biologic therapy. They must not have had hormonal therapy, chemotherapy or biologic therapy within 4 weeks prior to entering the study (6 weeks for nitrosoureas or mitomycin C, or UCN-01). Patients must be greater than or equal 2 weeks since any prior administration of study drug in a Phase 0 study (also referred to as an "early Phase I study" or "pre-Phase I study" where a sub-therapeutic dose of drug is administered) at the PI's discretion. Patients must be greater than or equal to 4 weeks since any prior radiation or major surgery. However, patients receiving bisphosphonates or therapeutic anticoagulation are eligible for this trial.
  • Age greater than or equal 18 years
  • The Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
  • Life expectancy > 3 months
  • Patients must have normal or adequate organ and marrow function as defined below:
  • Absolute neutrophil count greater than or equal to 1,500/microL
  • Platelets greater than or equal to 100,000/microL
  • Total bilirubin within less than or equal to 1.5 times institutional upper limit of normal
  • AST (SGOT)/ALT (SGPT) less than or equal to 2.5 times institutional upper limit of normal
  • Creatinine < 1.5 times upper limit of normal
  • OR
  • Creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with creatinine levels greater than or equal to 1.5 times upper limit of normal.
  • The effects of Z-endoxifen on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate nonhormonal contraception (barrier method of birth control or abstinence) prior to study entry, for the duration of study participation, and for 2 months after discontinuation from the study. Women of childbearing potential must have a negative pregnancy test in order to be eligible. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Z-endoxifen, breastfeeding should be discontinued if the mother is treated with Z-endoxifen.
  • Ability to understand and the willingness to sign a written informed consent document.

Who cannot join

  • Patients receiving any other investigational agents.
  • Patients with known brain metastases are excluded from this clinical trial, with the exception of patients whose brain metastatic disease status has remained stable for greater than or equal to 3 months after treatment of the brain metastases, without steroids or anti-seizure medications. These patients may be enrolled at the discretion of the principal investigator.
  • Patients with clinically significant illnesses which could compromise participation in the study, including, but not limited to, uncontrolled infection, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, stroke/cerebrovascular accident within the past 6 months, or psychiatric illness/social situations that in the investigator s opinion would make it undesirable for the patient to participate in the trial, or which would jeopardize compliance with the protocol.
  • Patients with untreated spinal cord metastases or metastases close to vital organs (as determined by the principal investigator) are excluded because of the risk of hormonal flare.
  • Patients with a history of deep vein thrombosis must be on anti-coagulation therapy prior to enrollment. Patients requiring prophylactic anti-coagulation are eligible.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center

    Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: Phase I Trial of Z-Endoxifen in Adults With Refractory Hormone Receptor-Positive Breast Cancer, Desmoid Tumors, Gynecologic Tumors, or Other Hormone Receptor-Positive Solid Tumors

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.
Read more

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.
Read the detailed description

Background:

Genetic polymorphisms in CYP2D6 and concomitant medications alter tamoxifen metabolism, limiting exposure to the active metabolite endoxifen. These factors are associated with a higher rate of recurrence and shorter disease-free survival in breast cancer patients receiving tamoxifen.

Administration of endoxifen directly to patients is anticipated to bypass the effects of CYP2D6 polymorphisms and concomitant medications and provide adequate active drug levels in all treated patients, resulting in clinical benefit.

16 alpha-[18F]-fluoro-17 beta-estradiol (FES) is an investigational radiolabeled imaging agent used with positron emission tomography (PET) to investigate tumor estrogen receptor activity.

Objectives:

Primary:

Establish the safety and tolerability of oral endoxifen (Z-Endoxifen HCl) administered on a daily schedule to patients with refractory hormone receptor-positive solid tumors (breast or other tumors), desmoid tumors, or gynecologic tumors.

Establish the maximum tolerated dose (MTD) of oral Z-endoxifen HCl administered on a daily schedule.

Secondary:

Determine the pharmacokinetics of oral Z-endoxifen (HCl form).

Exploratory:

Evaluate the change in [18F]FES uptake using PET/CT in hormone receptor-positive tumors before and after treatment with oral Z endoxifen HCl.

Eligibility:

Adults with histologically documented hormone receptor-positive solid tumors (breast or other tumors), desmoid tumors, or gynecologic tumors.

Patients with breast cancer must have had at least one prior chemotherapy regimen and one prior hormonal regimen for metastatic disease. All other patients must have disease that has progressed following at least one line of standard therapy.

No major surgery, radiation, hormonal, or chemotherapy within 4 weeks prior to study enrollment, and recovered from toxicities of prior therapies to at least eligibility levels.

Patients in the 6-patient expansion cohort at the MTD will be asked to undergo optional tumor biopsies for research purposes.

Study Design:

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

Dose escalation will proceed until the MTD is established or targeted maximum dose (DL8) reached. Six additional patients will then be entered in an expansion cohort to assess pharmacodynamics and pharmacokinetics.

When imaging agent is available, optional FES PET/CT scans will be performed at baseline and 1-3 hours after Z-endoxifen treatment once during week 1 of cycle 1.

As a relative bioavailability study, 6 patients in the expansion cohort will be given a single dose of the free base form of Z-endoxifen on day 1 and will then continue on study taking Z-endoxifen HCl; blood and urine will be collected for PK at baseline, on cycle 1 days 1 and 2, and on cycle 2 day 1. Please note: As of Febuary 2017, we will no longer evaluate the free base form of Z-endoxifen in the expansion cohort due to drug supply issues.

Being tested
Z-Endoxifen
Keywords
Pharmacokinetics, Advanced Cancer, Cytochrome P450, Selective Estrogen Receptor Modulator, Tamoxifen Metabolite, Gynecologic Cancer, Breast Cancer, Desmoid Tumor, Endometrial Cancer, Ovarian Cancer, Uterine Cancer, Fallopian Tube Cancer, Peritoneal Cancer
Medical subject headings
Desmoid Tumors, Breast Neoplasms, Endometrial Neoplasms, Ovarian Neoplasms, Uterine Neoplasms, Fallopian Tube Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Z-EndoxifenDrug

    Genetic polymorphisms in CYP2D6 and concomitant medications alter tamoxifen metabolism, limiting exposure to the active metabolite endoxifen. These factors are associated with a higher rate of recurrence and shorter disease-free survival in breast cancer patients receiving tamoxifen. Administration of endoxifen directly to patients is anticipated to bypass the effects of CYP2D6 polymorphisms and concomitant medications and provide adequate active drug levels in all treated patients, resulting in clinical benefit.

Study groups in NCT01273168
Study groupRoleWhat they receive
1ExperimentalZ-endoxifen will be administered orally once a day in 28-day cycles
Receives: Drug: Z-Endoxifen

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Establish safety and MTD of Z-endoxifen

    Adverse events will be graded as described in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

    Measured: 28 days (1 cycle)

Secondary outcomes (1)

  1. Determine the pharmacokinetics of Z-endoxifen (free base and HCl forms)

    Measured: 28 days (1 cycle)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 Jan 2011 (estimated)
  2. Study start1 Mar 2011
  3. Primary completion1 Jun 2020
  4. Study completion19 Dec 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
40 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01273168
Sponsor's protocol ID
110061
Other IDs
11-C-0061
Status last verified
Dec 2025
First submitted
7 Jan 2011
Last updated
23 Dec 2025
Results posted
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: All IPD recorded in the medical record will be shared with intramural investigators upon request.@@@@@@All collected IPD will be shared with collaborators under the terms of collaborative agreements.

Publications

  • Goetz MP, Suman VJ, Reid JM, Northfelt DW, Mahr MA, Ralya AT, Kuffel M, Buhrow SA, Safgren SL, McGovern RM, Black J, Dockter T, Haddad T, Erlichman C, Adjei AA, Visscher D, Chalmers ZR, Frampton G, Kipp BR, Liu MC, Hawse JR, Doroshow JH, Collins JM, Streicher H, Ames MM, Ingle JN. First-in-Human Phase I Study of the Tamoxifen Metabolite Z-Endoxifen in Women With Endocrine-Refractory Metastatic Breast Cancer. J Clin Oncol. 2017 Oct 20;35(30):3391-3400. doi: 10.1200/JCO.2017.73.3246. Epub 2017 Aug 30.

    PubMed 28854070

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Z-Endoxifen in people with Hormone Receptor-Positive Breast and Gynecologic, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 22 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 23 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Establish safety and MTD of Z-endoxifen (time frame: 28 days (1 cycle)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01273168, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Dec 2025.

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