(Z)-Endoxifen for the Treatment of Premenopausal Women With ER+/HER2- Breast Cancer
- Conditions
- Breast NeoplasmsInvasive Breast CancerEstrogen-receptor-positive Breast CancerHER2-negative Breast Cancer
- Interventions
- Registration Number
- NCT05607004
- Lead Sponsor
- Atossa Therapeutics, Inc.
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- Female
- Target Recruitment
- 214
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Female sex assigned at birth
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Age 18 years or older
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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.
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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
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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
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Pathologic confirmation of strongly estrogen receptor positive (ER+) (defined as estrogen receptor [ER] ≥ 67% or Allred Score 6-8) by local institution protocol
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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
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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
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Eastern Cooperative Oncology Group ECOG Performance Status (ECOG PS) of 0 to 2
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Nottingham (Elston-Ellis) Grade 1 or 2
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HER2- breast cancer (histologically confirmed) using American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines
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Clinical T2 or T3 invasive breast cancer (per American Joint Committee on Cancer [AJCC] 8th edition clinical staging)
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Clinical N0 or N1 invasive breast cancer (per American Joint Committee on Cancer [AJCC] 8th edition clinical staging)
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MRI ≤ 35 days of registration
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Mammogram performed ≤ 90 days of registration (Treatment Cohort Parts 2a and 2b only)
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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
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Willing to provide blood and breast tissue samples for research purposes at specified timepoints for the duration of their participation in the trial.
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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)
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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
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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
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Any of the following co-morbid conditions:
- Known cataracts or retinopathy
- History of deep vein thrombosis (DVT)/pulmonary embolism (PE)
- Known activated protein C (APC) resistance, an inherited coagulation disorder
- End stage kidney disease requiring dialysis
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Evidence of the following laboratory abnormalities ≤ 28 days prior to registration:
- Total bilirubin ≥ 1.5 x upper limit of normal (ULN)
- Aspartate aminotransferase (AST) or alanine amino transferase (ALT) ≥ 2.5 x ULN
- Platelet count (PLT) ≤ 75,000/mm3
- Hemoglobin (Hb) ≤ 10 g/dL
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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.
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Allergy to endoxifen, goserelin, or exemestane or any of their components
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Participation in another investigational clinical trial ≤ 6 months of registration
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Known metastatic disease
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History of polycystic ovarian syndrome (Treatment Cohort Part 2b ONLY)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Treatment Cohort Part 2a Arm 1 Initial Regimen goserelin Participants with Ki-67 value of \>10% at Pre-registration visit: (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 be offered to switch treatment to Exemestane 25 mg orally once daily + goserelin 3.6 mg by subcutaneous implant for 4 weeks and then collect Ki-67 value either by a breast biopsy or go on to surgery. Treatment Cohort Part 2a Arm 2 Initial Regimen exemestane Participants with Ki-67 value of \>10% at Pre-registration visit: Exemestane 25 mg orally once daily for 4 weeks + goserelin 3.6 mg by subcutaneous implant approximately every 28 days. 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. Treatment Cohort Part 2a Arm 2 Initial Regimen goserelin Participants with Ki-67 value of \>10% at Pre-registration visit: Exemestane 25 mg orally once daily for 4 weeks + goserelin 3.6 mg by subcutaneous implant approximately every 28 days. 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. Treatment Cohort Part 2a Arm 1 Modified Regimen exemestane Exemestane 25 mg orally once daily for 4 weeks + goserelin 3.6 mg by subcutaneous implant approximately every 28 days. After 4 weeks of modified regimen, Ki-67 value will be collected by breast biopsy or surgery. Early termination assessments will follow. Treatment Cohort Part 2a Arm 1 Modified Regimen goserelin Exemestane 25 mg orally once daily for 4 weeks + goserelin 3.6 mg by subcutaneous implant approximately every 28 days. After 4 weeks of modified regimen, Ki-67 value will be collected by breast biopsy or surgery. Early termination assessments will follow. PK Cohort 80 mg + OFS goserelin (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. PK Cohort (Z)-endoxifen (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. Treatment Cohort Part 2a Arm 1 Initial Regimen (Z)-endoxifen Participants with Ki-67 value of \>10% at Pre-registration visit: (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 be offered to switch treatment to Exemestane 25 mg orally once daily + goserelin 3.6 mg by subcutaneous implant for 4 weeks and then collect Ki-67 value either by a breast biopsy or go on to surgery. PK Cohort 80 mg (Z)-endoxifen (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. PK Cohort 80 mg + OFS (Z)-endoxifen (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. Treatment Cohort Part 2b Single Arm (Z)-endoxifen Participants with Ki-67 value of ≤ 10% at Pre-registration visit: (Z)-endoxifen 40 mg capsules orally once daily for 4 weeks. 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. And then go on to surgery. If Ki-67 \> 10% at Week 4, participant will complete early termination visit and go on to surgery.
- Primary Outcome Measures
Name Time Method PK Cohort - (Z)-endoxifen steady-state plasma concentrations After 4 weeks of treatment (Z)-endoxifen steady-state plasma concentrations (Css) of evaluable subjects who completed at least one cycle of treatment (28 +/- 3 days)
Treatment Cohort Part 2a - Endocrine sensitive disease rate based on Ki-67 percent after 4 weeks of treatment 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
Treatment Cohort Part 2b - Endocrine sensitive disease rate based on Ki-67 percentage after 24 weeks of treatment. After 24 weeks of treatment Endocrine sensitive disease rate will be estimated as the percentage of subjects whose surgical tumor biopsy finds Ki-67 less than or equal to 10 percent among evaluable subjects who began protocol treatment.
- Secondary Outcome Measures
Name Time Method PK Cohort - Area under the plasma (Z)-endoxifen concentration-time curve from time zero to last measurable concentration Days 1 and 28 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)
PK Cohort - Area under the plasma (E)-endoxifen concentration-time curve from time zero to last measurable concentration Days 1 and 28 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)
PK Cohort - Accumulation and accumulation half-life Days 1 and 28 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)
PK Cohort - (Z)-endoxifen steady-state clearance up to 28 days (Z)-endoxifen CLss (steady-state clearance) of evaluable subjects who completed at least one cycle of treatment (28 +/- 3 days)
PK Cohort - (E)-endoxifen steady-state clearance up to 28 days (E)-endoxifen CLss (steady-state clearance) of evaluable subjects who completed at least one cycle of treatment (28 +/- 3 days)
PK Cohort - Maximum plasma (Z)-endoxifen concentration up to 28 days Maximum plasma (Z)-endoxifen concentration (Cmax) of evaluable subjects who completed at least one cycle of treatment (28 +/- 3 days)
PK Cohort - Maximum plasma (E)-endoxifen concentration up to 28 days Maximum plasma (E)-endoxifen concentration (Cmax) of evaluable subjects who completed at least one cycle of treatment (28 +/- 3 days)
PK Cohort - Time to plasma (Z)-endoxifen maximum concentration up to 28 days Time to plasma (Z)-endoxifen maximum concentration (Tmax) of evaluable subjects who completed at least one cycle of treatment (28 +/- 3 days)
PK Cohort - Time to plasma (E)-endoxifen maximum concentration up to 28 days Time to plasma (E)-endoxifen maximum concentration (Tmax) of evaluable subjects who completed at least one cycle of treatment (28 +/- 3 days)
PK Cohort - plasma (Z)-endoxifen concentration Day 1 up to 12 weeks and up to end of treatment or up to 24 weeks. Trough concentrations of (Z)-endoxifen for subjects in the Treatment Extension
PK Cohort - plasma (E)-endoxifen concentration Day 1 up to 12 weeks and up to end of treatment or up to 24 weeks. Trough concentrations of (Z)-endoxifen for subjects in the Treatment Extension
PK Cohort and Treatment Cohort Part 2a- Endocrine sensitive disease rate based on Ki-67 percent after 4 weeks of treatment 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
Both Cohorts - Incidence of Adverse Events assessed by CTCAE version 5.0 Informed consent up to follow up visit or up to 30 weeks Incidence and severity of adverse events per CTCAE by treatment
Both Cohorts - Incidence of Serious Adverse Events assessed by CTCAE version 5.0 Informed consent up to follow up visit or up to 30 weeks Incidence of serious adverse events by treatment
Both Cohorts - Incidence of Adverse Events Leading to Discontinuation Informed consent up to end of treatment or up to 24 weeks Incidence of adverse events leading to discontinuation by treatment
Both Cohorts - Incidence of Dose Reductions Day 1 up to time of surgery or up to 27 weeks Proportion of patients who required a dose reduction by treatment arm
Both Cohorts - Change in estradiol and estrone Day 1, up to 4 weeks, up to 12 weeks and up to end of treatment or up to 24 weeks. Median percent change in the E1/E2 ratio
Both Cohorts - Percentage of subjects whose serum thymidine kinase 1 (TK1) falls below the detection limit after 4 weeks of treatment and 24 weeks. Day 1, up to 4 weeks, up to 12 weeks and up to end of treatment or up to 24 weeks. Percentage of subjects whose serum TK1 falls below the detection limit (\< 20 DiviTum units per liter Du/L) after one cycle of treatment among those with detectable serum TK1 levels prior to start of protocol treatment
Both Cohorts - Changes from baseline Informed consent up to follow up visit or up to 30 weeks Changes from baseline in vital signs, physical examination findings, clinical laboratory parameters, ECG findings
Both Cohorts - Assess additional PK parameters of (Z)-endoxifen and (E)-endoxifen Day 1, up to 4 weeks, up to 12 weeks and up to 24 weeks Tissue and plasma (Z)-endoxifen and (E)-endoxifen concentrations at 4 weeks and 24 weeks
Treatment Cohort - Radiographic Response Rate in the breast Baseline Assessment, up to 4 weeks, up to 12 weeks, and up to 24 weeks Radiographic response rate in the breast at 4, 12, and 24 weeks as assessed by RECIST 1.1 criteria
Treatment Cohort - Pathologic Complete Response per American Joint Committee on Cancer staging system at time of surgery At time of surgery or up to 27 weeks 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
Treatment Cohort - Pre-Operative Endocrine Prognostic Index at time of surgery At time of surgery or up to 27 weeks Rate of Pre-Operative Endocrine Prognostic Index (PEPI) 0 at time of surgery using residual tumor specimen
Treatment Cohort - Residual Cancer Burden at time of surgery At time of surgery or up to 27 weeks Rate of residual cancer burden class of 0-I at time of surgery
Treatment Cohort - Conversion Rate From baseline to time of surgery or up to 27 weeks Evaluate the conversion rate from breast conservation surgery ineligible to breast conservation surgery eligible. Evaluation is based on surgeon's impression of the type of surgery participant is eligible for (candidate for lumpectomy, candidate for modified radical mastectomy, inoperable) at baseline compared to surgeon's impression after completion of neoadjuvant treatment
Treatment Cohort - Actual Conversion Rate At time of surgery or up to 27 weeks Evaluate the actual rate of breast conservation surgery. Evaluation will be based on the extent of the surgical procedure at the time of surgery (lumpectomy, partial or segmental mastectomy, simple/total mastectomy, skin and/or nipple sparing mastectomy, radical mastectomy or other)
Treatment Cohort - Change in blood pressure baseline, up to 4 weeks, and up to 24 weeks Change from pre-neoadjuvant treatment in blood pressure
Treatment Cohort Part 2b - safety and tolerability of (Z)-endoxifen monotherapy Day 1 up to week 24 Incidence and severity of ovarian cysts as documented by pelvic ultrasound
Treatment Cohort - Change in fasting glucose baseline, up to 4 weeks, and up to 24 weeks Change from pre-neoadjuvant treatment in fasting glucose
Treatment Cohorts - Change in menopause quality of life (MENQOL) baseline, up to 4 weeks, and up to 24 weeks Evaluate changes in menopause symptoms after neoadjuvant treatment
Treatment Cohorts - Change in mammographic density area (cm2) baseline up to Week 24 Change in mammographic breast density area (cm2) assessed by iCAD®
Treatment Cohorts - Nodal response rate At time of surgery or up to 27 weeks Rate of nodal pCR in subjects with biopsy proven nodal disease
Trial Locations
- Locations (12)
Tranquility Research
🇺🇸Webster, Texas, United States
Bon Secours Cancer Institute
🇺🇸Midlothian, Virginia, United States
Mayo Clinic Arizona
🇺🇸Phoenix, Arizona, United States
University of Arizona
🇺🇸Tucson, Arizona, United States
Mayo Clinic Florida
🇺🇸Jacksonville, Florida, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
St. Elizabeth Healthcare
🇺🇸Edgewood, Kentucky, United States
Henry Ford Cancer Institute
🇺🇸Detroit, Michigan, United States
Mayo Clinic Rochester
🇺🇸Rochester, Minnesota, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Avera Cancer Institute
🇺🇸Sioux Falls, South Dakota, United States
Vanderbilt Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States