Clinical trial NCT05607004: (Z)-Endoxifen for the Treatment of Premenopausal Women With ER+/HER2- Breast Cancer
Official title: A Randomized Phase 2 Non-inferiority Trial of (Z)-Endoxifen + Goserelin Versus Exemestane + Goserelin as Neoadjuvant Treatment for Premenopausal Women With ER+, HER2-, Ki-67>10% Breast Cancer and a Single Arm Phase 2 Study of (Z)-Endoxifen as Neoadjuvant Treatment for Premenopausal Women With ER+, HER2-, Ki-67 ≤ 10% Breast Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
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
Lead sponsor: Atossa Therapeutics, Inc.
Sponsor class: INDUSTRY
Collaborators: name: InClin
First posted: 2022-11-07
Enrollment: 214
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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 two parts. Part 2a includes participants with diagnostic Ki-67 \>10% randomized 1:1 to a two-arm study with potential for one arm to switch regimens based on Ki-67% at Week 4. Part 2b includes study participants with a diagnostic Ki-67 ≤ 10% assigned to a single arm monotherapy.
Primary purpose: TREATMENT

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 part has two parts:

* Part 2a will enroll 162 participants whose tumors have a high level of cell proliferation as indicated by the presence of a biomarker called Ki-67 (greater than 10%). Participants will be randomly assigned to one of two groups (50/50 chance):

  1. a group receiving (Z)-endoxifen daily with a monthly injection of goserelin
  2. a group receiving the current standard treatment of exemestane (an aromatase inhibitor that lowers estrogen) with a monthly injection of goserelin.
* The Part 2b will enroll about 30 participants whose tumors have low Ki-67 levels (10% or less). These participants will take daily (Z)-endoxifen alone without goserelin.

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.


Eligibility criteria: Inclusion Criteria:

1. Female sex assigned at birth
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. Treatment Cohort Part 2a, Randomized Treatment Cohort: Local pathology laboratory finding of Ki-67 \> 10% in invasive breast cancer specimen obtained at or after diagnosis but prior to any anti-tumor treatment
8. Treatment Cohort Part 2b, Single Arm Treatment Cohort: Local pathology laboratory finding of Ki- ≤ 10% in invasive breast cancer specimen obtained at or after diagnosis but prior to any anti-tumor treatment
9. Eastern Cooperative Oncology Group ECOG Performance Status (ECOG PS) of 0 to 2
10. Nottingham (Elston-Ellis) Grade 1 or 2
11. HER2- breast cancer (histologically confirmed) using American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines
12. Clinical T2 or T3 invasive breast cancer (per American Joint Committee on Cancer \[AJCC\] 8th edition clinical staging)
13. Clinical N0 or N1 invasive breast cancer (per American Joint Committee on Cancer \[AJCC\] 8th edition clinical staging)
14. MRI ≤ 35 days of registration
15. Mammogram performed ≤ 90 days of registration (Treatment Cohort Parts 2a and 2b only)
16. 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
17. 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
10. History of polycystic ovarian syndrome (Treatment Cohort Part 2b ONLY)

Primary outcomes:
measure: PK Cohort - (Z)-endoxifen steady-state plasma concentrations
timeFrame: After 4 weeks of treatment
measure: Treatment Cohort Part 2a - Endocrine sensitive disease rate based on Ki-67 percent after 4 weeks of treatment
timeFrame: After 4 weeks of treatment
measure: Treatment Cohort Part 2b - Endocrine sensitive disease rate based on Ki-67 percentage after 24 weeks of treatment.
timeFrame: After 24 weeks of treatment
Secondary outcomes:
measure: PK Cohort - Area under the plasma (Z)-endoxifen concentration-time curve from time zero to last measurable concentration
timeFrame: Days 1 and 28
measure: PK Cohort - Area under the plasma (E)-endoxifen concentration-time curve from time zero to last measurable concentration
timeFrame: Days 1 and 28
measure: PK Cohort - Accumulation and accumulation half-life
timeFrame: Days 1 and 28
measure: PK Cohort - (Z)-endoxifen steady-state clearance
timeFrame: up to 28 days
measure: PK Cohort - (E)-endoxifen steady-state clearance
timeFrame: up to 28 days
measure: PK Cohort - Maximum plasma (Z)-endoxifen concentration
timeFrame: up to 28 days
measure: PK Cohort - Maximum plasma (E)-endoxifen concentration
timeFrame: up to 28 days
measure: PK Cohort - Time to plasma (Z)-endoxifen maximum concentration
timeFrame: up to 28 days
measure: PK Cohort - Time to plasma (E)-endoxifen maximum concentration
timeFrame: up to 28 days
measure: PK Cohort - plasma (Z)-endoxifen concentration
timeFrame: Day 1 up to 12 weeks and up to end of treatment or up to 24 weeks.
measure: PK Cohort - plasma (E)-endoxifen concentration
timeFrame: Day 1 up to 12 weeks and up to end of treatment or up to 24 weeks.
measure: PK Cohort and Treatment Cohort Part 2a- Endocrine sensitive disease rate based on Ki-67 percent after 4 weeks of treatment
timeFrame: After 4 weeks of treatment
measure: Both Cohorts - Incidence of Adverse Events assessed by CTCAE version 5.0
timeFrame: Informed consent up to follow up visit or up to 30 weeks
measure: Both Cohorts - Incidence of Serious Adverse Events assessed by CTCAE version 5.0
timeFrame: Informed consent up to follow up visit or up to 30 weeks
measure: Both Cohorts - Incidence of Adverse Events Leading to Discontinuation
timeFrame: Informed consent up to end of treatment or up to 24 weeks
measure: Both Cohorts - Incidence of Dose Reductions
timeFrame: Day 1 up to time of surgery or up to 27 weeks
measure: Both Cohorts - Change in estradiol and estrone
timeFrame: Day 1, up to 4 weeks, up to 12 weeks and up to end of treatment or up to 24 weeks.
measure: Both Cohorts - Percentage of subjects whose serum thymidine kinase 1 (TK1) falls below the detection limit after 4 weeks of treatment and 24 weeks.
timeFrame: Day 1, up to 4 weeks, up to 12 weeks and up to end of treatment or up to 24 weeks.
measure: Both Cohorts - Changes from baseline
timeFrame: Informed consent up to follow up visit or up to 30 weeks
measure: Both Cohorts - Assess additional PK parameters of (Z)-endoxifen and (E)-endoxifen
timeFrame: Day 1, up to 4 weeks, up to 12 weeks and up to 24 weeks
measure: Treatment Cohort - Radiographic Response Rate in the breast
timeFrame: Baseline Assessment, up to 4 weeks, up to 12 weeks, and up to 24 weeks
measure: Treatment Cohort - Pathologic Complete Response per American Joint Committee on Cancer staging system at time of surgery
timeFrame: At time of surgery or up to 27 weeks
measure: Treatment Cohort - Pre-Operative Endocrine Prognostic Index at time of surgery
timeFrame: At time of surgery or up to 27 weeks
measure: Treatment Cohort - Residual Cancer Burden at time of surgery
timeFrame: At time of surgery or up to 27 weeks
measure: Treatment Cohort - Conversion Rate
timeFrame: From baseline to time of surgery or up to 27 weeks
measure: Treatment Cohort - Actual Conversion Rate
timeFrame: At time of surgery or up to 27 weeks
measure: Treatment Cohort - Change in blood pressure
timeFrame: baseline, up to 4 weeks, and up to 24 weeks
measure: Treatment Cohort Part 2b - safety and tolerability of (Z)-endoxifen monotherapy
timeFrame: Day 1 up to week 24
measure: Treatment Cohort - Change in fasting glucose
timeFrame: baseline, up to 4 weeks, and up to 24 weeks
measure: Treatment Cohorts - Change in menopause quality of life (MENQOL)
timeFrame: baseline, up to 4 weeks, and up to 24 weeks
measure: Treatment Cohorts - Change in mammographic density area (cm2)
timeFrame: baseline up to Week 24
measure: Treatment Cohorts - Nodal response rate
timeFrame: At time of surgery or up to 27 weeks
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Jacksonville
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Edgewood
country: United States
facility: St. Elizabeth Healthcare
state: Kentucky
city: Detroit
country: United States
facility: Henry Ford Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Sioux Falls
country: United States
facility: Avera Cancer Institute
state: South Dakota
city: Nashville
country: United States
facility: Vanderbilt Ingram Cancer Center
state: Tennessee
city: Webster
country: United States
facility: Tranquility Research
state: Texas
city: Midlothian
country: United States
facility: Bon Secours Cancer Institute
state: Virginia
Study officials:
affiliation: Mayo Clinic
name: Matthew P Goetz, MD
role: PRINCIPAL_INVESTIGATOR
References: