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

Phase 2RecruitingNCT05607004

Atossa Therapeutics, Inc.87 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. 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. 2. Age 18 years or older 3. 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. 4. 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 5. Premenopausal defined as any female who: 1. is menstruating or 2. is not menstruating (last menstrual period \> 3 months prior to registration) but has a plasma estradiol in the premenopausal range as assessed locally 6. Pathologic confirmation of strongly estrogen receptor positive (ER+) (defined as estrogen receptor \[ER\] ≥ 67% or Allred Score 6-8) by local institution protocol 7. Eastern Cooperative Oncology Group ECOG Performance Status (ECOG PS) of 0 to 2 8. Nottingham (Elston-Ellis) Grade 1 or 2 9. HER2- breast cancer (histologically confirmed) using American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines 10. Clinical T2 or T3 invasive breast cancer (per American Joint Committee on Cancer \[AJCC\] 8th edition clinical staging) 11. Clinical N0 or N1 invasive breast cancer (per American Joint Committee on Cancer \[AJCC\] 8th edition clinical staging) 12. MRI ≤ 35 days of registration 13. 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 14. Willing to provide blood and breast tissue samples for research purposes at specified timepoints for the duration of their participation in the trial. Exclusion Criteria: 1. 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) 2. 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: 1. Adequately treated in situ carcinoma of the cervix uteri 2. Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin 3. Any other malignancy with a life expectancy of less than 2 years 3. Any uncontrolled intercurrent illness including, but not limited to: 1. Ongoing or active infection requiring systemic treatment with strong inhibitors/inducers of CYP450 enzymes (including bacterial infection, fungal infection, or detectable viral infection). 2. Symptomatic congestive heart failure, 3. Unstable angina pectoris, 4. Uncontrolled symptomatic cardiac arrhythmias 5. Uncontrolled hypertension 6. Uncontrolled diabetes (Hemoglobin A1c \[HbA1c\] \>7%) 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 4. Any of the following co-morbid conditions: 1. Known cataracts or retinopathy 2. History of deep vein thrombosis (DVT)/pulmonary embolism (PE) 3. Known activated protein C (APC) resistance, an inherited coagulation disorder 4. End stage kidney disease requiring dialysis 5. Evidence of the following laboratory abnormalities ≤ 28 days prior to registration: 1. Total bilirubin ≥ 1.5 x upper limit of normal (ULN) 2. Aspartate aminotransferase (AST) or alanine amino transferase (ALT) ≥ 2.5 x ULN 3. Platelet count (PLT) ≤ 75,000/mm3 4. Hemoglobin (Hb) ≤ 10 g/dL 6. Hormonal therapies including birth control and hormone replacement therapy, or prior use of androgen-based therapy during the study or within 1 week of registration. If subject has a prior medical history of Depo-Provera®, it is recommended that the last dose of 3-month contraceptive agents are \> 2.5 months from registration. 7. Allergy to endoxifen, goserelin, or exemestane or any of their components 8. Participation in another investigational clinical trial ≤ 6 months of registration 9. Known metastatic disease

Locations (15)

Mayo Clinic Arizona

Phoenix, Arizona, United States

RECRUITING

University of Arizona

Tucson, Arizona, United States

RECRUITING

California Research Institute

Los Angeles, California, United States

RECRUITING

Mayo Clinic Florida

Jacksonville, Florida, United States

RECRUITING

Northwestern University

Chicago, Illinois, United States

RECRUITING

St. Elizabeth Healthcare

Edgewood, Kentucky, United States

RECRUITING

Henry Ford Cancer Institute

Detroit, Michigan, United States

RECRUITING

Mayo Clinic Rochester

Rochester, Minnesota, United States

RECRUITING

Washington University School of Medicine

St Louis, Missouri, United States

RECRUITING

Avera Cancer Institute

Sioux Falls, South Dakota, United States

RECRUITING

...and 5 more locations

Outcomes

Primary Outcomes

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)

Time frame: 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.

Time frame: 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.

Time frame: After 24 weeks of treatment

Secondary Outcomes

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

Area under the plasma (Z)-endoxifen concentration-time curve from time zero to last measurable concentration (AUC0-24) on Days 1 and 28 of evaluable subjects who completed at least one cycle of treatment (28 +/- 3 days)

Time frame: Days 1 and 28

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

Area under the plasma (E)-endoxifen concentration-time curve from time zero to last measurable concentration (AUC0-24) on Days 1 and 28 of evaluable subjects who completed at least one cycle of treatment (28 +/- 3 days)

Time frame: Days 1 and 28

PK Cohort - Accumulation and accumulation half-life

Accumulation and accumulation half-life (Day 28 AUC0-24/Day 1 AUC0-24) of evaluable subjects who completed at least one cycle of treatment (28 +/- 3 days)

Time frame: Days 1 and 28

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

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

Time frame: up to 28 days

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

(E)-endoxifen CLss (steady-state clearance) of evaluable subjects who completed at least one cycle of treatment (28 +/- 3 days)

Time frame: up to 28 days

PK Cohort - Maximum plasma (Z)-endoxifen concentration

Maximum plasma (Z)-endoxifen concentration (Cmax) of evaluable subjects who completed at least one cycle of treatment (28 +/- 3 days)

Time frame: up to 28 days

PK Cohort - Maximum plasma (E)-endoxifen concentration

Maximum plasma (E)-endoxifen concentration (Cmax) of evaluable subjects who completed at least one cycle of treatment (28 +/- 3 days)

Time frame: up to 28 days

PK Cohort - Time to plasma (Z)-endoxifen maximum concentration

Time to plasma (Z)-endoxifen maximum concentration (Tmax) of evaluable subjects who completed at least one cycle of treatment (28 +/- 3 days)

Time frame: up to 28 days

PK Cohort - Time to plasma (E)-endoxifen maximum concentration

Time to plasma (E)-endoxifen maximum concentration (Tmax) of evaluable subjects who completed at least one cycle of treatment (28 +/- 3 days)

Time frame: up to 28 days

PK Cohort - plasma (Z)-endoxifen concentration

Trough concentrations of (Z)-endoxifen for subjects in the Treatment Extension

Time frame: Day 1 up to 12 weeks and up to end of treatment or up to 24 weeks.

PK Cohort - plasma (E)-endoxifen concentration

Trough concentrations of (Z)-endoxifen for subjects in the Treatment Extension

Time frame: Day 1 up to 12 weeks and up to end of treatment or up to 24 weeks.

PK Cohort- Endocrine sensitive disease rate based on Ki-67 percent after 4 weeks of treatment

Endocrine sensitive disease rate will be estimated as the percentage of subjects whose 4-week tumor biopsy finds Ki-67 less than or equal to 10 percent among evaluable subjects who began protocol treatment

Time frame: After 4 weeks of treatment

All Cohorts - Incidence and severity of adverse events per CTCAE by treatment

Incidence and severity of adverse events per CTCAE

Time frame: Informed consent up to follow up visit or up to 30 weeks

All Cohorts - Incidence of Serious Adverse Events assessed by CTCAE version 5.0

Serious adverse events and adverse events leading to discontinuation of neoadjuvant treatment

Time frame: Informed consent up to follow up visit or up to 30 weeks

All Cohorts - Incidence of Dose Reductions

The incidence of dose reductions

Time frame: Informed consent up to end of treatment or up to 24 weeks

All Cohorts - Change in estradiol and estrone

Percent change from baseline in E1 and E2 at 4 weeks, and 24 weeks

Time frame: Day 1, up to 4 weeks and up to end of treatment or up to 24 weeks.

All Cohorts - Percentage of subjects whose serum thymidine kinase 1 (TK1) is not detectable at 4 weeks and 24 weeks.

Percent of subjects whose serum TK1 is not detectable at 4 weeks and 24 weeks

Time frame: Day 1, up to 4 weeks and up to end of treatment or up to 24 weeks.

Treatment Cohorts - Assess additional PK parameters of (Z)-endoxifen and (E)-endoxifen

Tissue and plasma (Z)-endoxifen and (E)-endoxifen concentrations at 4 weeks and 24 weeks

Time frame: Day 1, up to 4 weeks, up to 12 weeks and up to 24 weeks

Treatment Cohorts - Radiographic Response Rate in the breast

Radiographic response rate in the breast at 4, 12, and 24 weeks as assessed by RECIST 1.1 criteria

Time frame: Baseline Assessment, up to 4 weeks, up to 12 weeks, and up to 24 weeks

Treatment Cohorts - Pathologic Complete Response per American Joint Committee on Cancer staging system at time of surgery

Pathologic Complete Response (pCR) at surgery defined as the absence of residual invasive breast cancer on hematoxylin and eosin evaluation of the resected breast specimen and of all sampled lymph nodes (sentinel ± axillary) removed following completion of neoadjuvant systemic therapy