(Z)-Endoxifen for the Treatment of Premenopausal Women With ER+/HER2- Breast Cancer

NCT05607004 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: ATOS-Z-201
• Study Type: interventional
• Target: 87
• Locations: 1 country
• Sites: 15

Brief Summary

This open-label research study is studying (Z)-endoxifen as a possible treatment for pre-menopausal women with ER+/HER2- breast cancer. (Z)-endoxifen belongs to a group of drugs called selective estrogen receptor modulators or "SERM", which help block estrogen from attaching to cancer cells. This study has two parts: a pharmacokinetic part and a treatment part. The PK part (how the body processes the drug) will enroll about 18 participants. All participants will take (Z)-endoxifen capsules daily. Twelve participants will be randomly assigned (50/50 chance) to take (Z)-endoxifen alone or (Z)-endoxifen with a monthly injection of goserelin a drug that temporarily stops the ovaries from making estrogen. This part will help determine the best dose of (Z)-endoxifen by measuring the drug levels in the blood and how long the body takes to remove it. The Treatment Cohort has been simplified to a single study arm (Z)-endoxifen + goserelin. Up to 20 participants will be enrolled that have a baseline Ki-67 ≤ 10% and 45 participants will be enrolled that have a baseline Ki-67\>10%. A key goal of the study is to see if (Z)-endoxifen can slow down or stop tumor growth as measured by a reduction in Ki-67 levels. Tumor tissue samples will be taken by breast biopsy after about 4 weeks of treatment to check levels of this biomarker. If the tumor shows signs of response, participants can continue treatment for up to 24 weeks or until they have surgery. Study participation is up to 6 months (24 weeks of treatment) followed by surgery and a one-month follow up visit.

Conditions

Breast Neoplasms; Invasive Breast Cancer; Estrogen-receptor-positive Breast Cancer; HER2-negative Breast Cancer

Keywords

breast cancer; ER+/HER2-; endocrine therapy; neoadjuvant; (Z)-endoxifen; exemestane; goserelin; Ki-67; estrogen receptor negative; human epidermal growth factor receptor 2 negative; Stage II; tamoxifen; PKCB1

Outcome Measures

Primary Outcomes (3)

• PK Cohort - (Z)-endoxifen steady-state plasma concentrations

  (Z)-endoxifen steady-state plasma concentrations (Css) of evaluable subjects who completed at least one cycle of treatment (28 +/- 3 days)

  After 4 weeks of treatment

• For Analysis of Cohort A (Treatment Cohort): determine whether the week 4 Ki-67≤10% rate is at least 65%

  For analysis Cohort A (subjects that have a baseline Ki-67\>10%): the primary objective is to determine whether the Week 4 Ki-67 ≤ 10% rate is at least 65% among premenopausal women with primary estrogen receptor positive (ER+), Human Epidermal Growth Factor Receptor 2 negative (HER2-) breast cancer.

  After 4 weeks of treatment

• For analysis Cohort B (Treatment Cohort): determine the objective tumor response rate at 24 weeks

  For analysis Cohort B (subjects have baseline Ki-67≤ 10%): the primary objective is to determine the objective tumor response rate at 24 weeks among premenopausal women with ER+, HER2-, Ki-67 ≤ 10% breast cancer receiving (Z) endoxifen plus goserelin.

  After 24 weeks of treatment

Secondary Outcomes (26)

• PK Cohort - Area under the plasma (Z)-endoxifen concentration-time curve from time zero to last measurable concentration

  Days 1 and 28

• PK Cohort - Area under the plasma (E)-endoxifen concentration-time curve from time zero to last measurable concentration

  Days 1 and 28

• PK Cohort - Accumulation and accumulation half-life

  Days 1 and 28

• PK Cohort - (Z)-endoxifen steady-state clearance

  up to 28 days

• PK Cohort - (E)-endoxifen steady-state clearance

  up to 28 days

Study Arms (4)

PK Cohort

EXPERIMENTAL

(Z)-endoxifen capsules orally once daily for 4 weeks. Initial (Z)-endoxifen dose evaluated will be 40 mg with an option to evaluate 20 mg or 80 mg. The PK Cohort participants may extend treatment based on Ki-67% at Week 4. If Ki-67 ≤ 10% at Week 4, participant will be offered option to continue on this treatment for up to 6 cycles/Week 24. Each cycle is 28 days. If Ki-67 \> 10% at Week 4, participant will be withdrawn and go on to surgery.

Drug: (Z)-endoxifen

Treatment Cohort - Single Treatment Arm

EXPERIMENTAL

(Z)-endoxifen 40mg capsules orally once daily for 4 weeks + goserelin 3.6 mg by subcutaneous implant approximately every 28 days. (Z)-endoxifen 40mg dose based on results of PK Cohort. If Ki-67 ≤ 10% at Week 4, continue on this treatment for up to 6 cycles/Week 24. Each cycle is 28 days. And then go on to surgery within 3 weeks of Cycle 6 day 26. If Ki-67 \> 10% at Week 4, participant will complete early termination assessments.

Drug: (Z)-endoxifen; Drug: goserelin

PK Cohort 80 mg

EXPERIMENTAL

(Z)-endoxifen 80 mg capsules orally once daily for 4 weeks. The PK Cohort participants may extend treatment based on Ki-67% at Week 4. If Ki-67 ≤ 10% at Week 4, participant will be offered option to continue on this treatment for up to 6 cycles/Week 24. Each cycle is 28 days. If Ki-67 \> 10% at Week 4, participant will be withdrawn and go on to surgery.

Drug: (Z)-endoxifen

PK Cohort 80 mg + OFS

EXPERIMENTAL

(Z)-endoxifen 80 mg capsules orally once daily for 4 weeks + goserelin 3.6 mg by subcutaneous implant approximately every 28 days. The PK Cohort participants may extend treatment based on Ki-67% at Week 4. If Ki-67 ≤ 10% at Week 4, participant will be offered option to continue on this treatment for up to 6 cycles/Week 24. Each cycle is 28 days. If Ki-67 \> 10% at Week 4, participant will be withdrawn and go on to surgery.

Drug: (Z)-endoxifen; Drug: goserelin

Interventions

(Z)-endoxifen DRUG

(Z)-endoxifen capsules. Doses of (Z)-endoxifen to be evaluated include 20 mg (two x 10 mg capsules), 40 mg (one 40 mg capsule) and 80 mg (two x 40 mg capsules).

Also known as: endoxifen

PK Cohort; PK Cohort 80 mg; PK Cohort 80 mg + OFS; Treatment Cohort - Single Treatment Arm

goserelin DRUG

goserelin 3.6 mg subcutaneous implant

Also known as: Zoladex

PK Cohort 80 mg + OFS; Treatment Cohort - Single Treatment Arm

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Female sex assigned at birth
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Female sex assigned at birth. Female to male transgender individuals who have not had any hormonal therapy may be considered for the trial after review and approval from the medical monitor and study sponsor.
• Age 18 years or older
• Not lactating, pregnant, or planning to become pregnant in the next year and agrees to take adequate steps to prevent becoming pregnant beginning at informed consent, during treatment and for 9 months after last dose and agree to not breast feed during treatment and for 3 months after last dose.
• Must agree to use at least one non-hormonal highly effective method of contraception for the entire duration of study participation beginning at informed consent. Highly effective methods of birth control are defined as those, alone or in combination, that resulted in a low failure rate of \<1% per year when used consistently and correctly such as intrauterine devices (IUDs, non-hormonal such as copper IUD), bilateral tubal occlusion, sexual abstinence or vasectomized partner
• Premenopausal defined as any female who:
• is menstruating or
• is not menstruating (last menstrual period \> 3 months prior to registration) but has a plasma estradiol in the premenopausal range as assessed locally
• Pathologic confirmation of strongly estrogen receptor positive (ER+) (defined as estrogen receptor \[ER\] ≥ 67% or Allred Score 6-8) by local institution protocol
• Eastern Cooperative Oncology Group ECOG Performance Status (ECOG PS) of 0 to 2
• Nottingham (Elston-Ellis) Grade 1 or 2
• HER2- breast cancer (histologically confirmed) using American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines
• Clinical T2 or T3 invasive breast cancer (per American Joint Committee on Cancer \[AJCC\] 8th edition clinical staging)
• Clinical N0 or N1 invasive breast cancer (per American Joint Committee on Cancer \[AJCC\] 8th edition clinical staging)
• MRI ≤ 35 days of registration
• Must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects

You may not qualify if:

• Bilateral invasive breast cancer; Inflammatory breast cancer defined as clinically significant erythema of the breast and/or documented dermal lymphatic invasion or bilateral invasive breast cancer (patients with pre-malignant disease or DCIS/LCIS in contralateral breast are eligible)
• Prior diagnosis or treatment for breast cancer, including carcinoma in situ, or history of any other active malignancy within the past 2 years prior to study entry with the exception of:
• Adequately treated in situ carcinoma of the cervix uteri
• Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin
• Any other malignancy with a life expectancy of less than 2 years
• Any uncontrolled intercurrent illness including, but not limited to:
• Ongoing or active infection requiring systemic treatment with strong inhibitors/inducers of CYP450 enzymes (including bacterial infection, fungal infection, or detectable viral infection).
• Symptomatic congestive heart failure,
• Unstable angina pectoris,
• Uncontrolled symptomatic cardiac arrhythmias
• Uncontrolled hypertension
• Uncontrolled diabetes (Hemoglobin A1c \[HbA1c\] \>7%)
• Marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval \> 470 milliseconds \[msec\]) using Fridericia's QT correction formula seen ≤ 28 days of registration
• Any of the following co-morbid conditions:
• Known cataracts or retinopathy

Sponsors & Collaborators

• Atossa Therapeutics, Inc.: lead
• InClin: collaborator

Study Sites (15)

Mayo Clinic Arizona

Phoenix, Arizona, 85054, United States

RECRUITING

University of Arizona

Tucson, Arizona, 85719, United States

RECRUITING

California Research Institute

Los Angeles, California, 90027, United States

RECRUITING

Mayo Clinic Florida

Jacksonville, Florida, 32224, United States

RECRUITING

Northwestern University

Chicago, Illinois, 60611, United States

RECRUITING

St. Elizabeth Healthcare

Edgewood, Kentucky, 41017, United States

RECRUITING

Henry Ford Cancer Institute

Detroit, Michigan, 48202, United States

RECRUITING

Mayo Clinic Rochester

Rochester, Minnesota, 55905, United States

RECRUITING

Washington University School of Medicine

St Louis, Missouri, 63110, United States

RECRUITING

Avera Cancer Institute

Sioux Falls, South Dakota, 57105, United States

RECRUITING

Vanderbilt Ingram Cancer Center

Nashville, Tennessee, 37204, United States

RECRUITING

Baylor University

Houston, Texas, 77054, United States

RECRUITING

Tranquility Research

Webster, Texas, 77598, United States

WITHDRAWN

Bon Secours Cancer Institute

Midlothian, Virginia, 23114, United States

RECRUITING

Fred Hutchinson Cancer Center

Seattle, Washington, 98109, United States

RECRUITING

MeSH Terms

Conditions

Breast Neoplasms

Interventions

4-hydroxy-N-desmethyltamoxifen; Goserelin

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins

Study Officials

• Matthew P Goetz, MD

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Hayley Erickson

CONTACT

206-486-1872; hayley.erickson@atossainc.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This multicenter open-label study consists of two cohorts: PK and Treatment The PK Cohort is a dose finding study to identify the dose to use in the Treatment Cohort. The Treatment Cohort includes a single treatment arm. All participants will be assigned to (Z)-endoxifen + goserelin.

Study Record Dates

• First Submitted: October 26, 2022
• First Posted: November 7, 2022
• Study Start: February 14, 2023
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): April 1, 2027
• Last Updated: October 30, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (15)