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

Study Overview
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Brief Summary
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This open-label research study is studying (Z)-endoxifen as a possible treatment for pre-menopausal (still having periods) women with ER+/HER2- breast cancer. (Z)-endoxifen is a selective estrogen receptor modulator or SERM. SERMs work to treat cancer by blocking the body's natural estrogen from binding to cancer cells. This study includes a pharmacokinetic part (PK, how the drug works in your body) and a treatment part. The primary purpose of the study is to see how (Z)-endoxifen works on tumor cell growth by monitoring a cancer marker called Ki-67. Ki-67 will be measured by biopsy of the breast after about 4 weeks of treatment. If your cancer is responding to treatment based on the Ki-67 results, you may continue treatment up to 24 weeks or until surgery. The PK part of the study will be enrolled first, enrolling about 18 study participants who will all receive oral once daily (Z)-endoxifen treatment. 12 of these participants will be randomly assigned to treatment with an equal (50/50) chance to be assigned to (Z)-endoxifen or (Z)-endoxifen + goserelin (a medication given to block the ovaries from making estrogen and is also called ovarian suppression). This part of the study will help select the dose of (Z)-endoxifen to use in the treatment part by measuring the levels of (Z)-endoxifen in the blood stream and determine how long it takes for the body to remove it. About 160 study participants will be enrolled in the treatment part. The treatment part will help to determine how oral once daily (Z)-endoxifen, when taken by itself, compares to oral once daily exemestane (a medication that decreases the amount of estrogen in the body, also known as an aromatase inhibitor) and monthly injections of goserelin. Exemestane and goserelin taken together is a standard treatment regimen for premenopausal patients with ER+/HER2- breast cancer. Study participants are randomly assigned to treatment with an equal (50/50) chance to be assigned to (Z)-endoxifen or standard treatment. Study participation is up to 24 weeks of treatment followed by surgery.

Official Title
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A Randomized Phase 2 Non-inferiority Trial of (Z)-Endoxifen and Exemestane + Goserelin as Neoadjuvant Treatment in Premenopausal Women With ER+/HER2- Breast Cancer

Conditions
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Estrogen-receptor-positive Breast Cancer, Breast Neoplasms, Invasive Breast Cancer, HER2-negative Breast Cancer

Intervention / Treatment
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* Drug: (Z)-endoxifen
* Drug: exemestane
* Drug: goserelin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Premenopausal women 18 years or older Not lactating, pregnant, or planning to become pregnant in the next year Agree to use at least one non-hormonal highly effective method of contraception for the entire duration of study participation. ER+/HER2-: [ER] ≥ 67% or Allred Score 6-8) / HER2- (histologically confirmed) using American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines Clinical T2 or T3 and N0 or N1 invasive breast cancer (per American Joint Committee on Cancer [AJCC] 8th edition clinical staging) Nottingham Grade 1 or 2 ECOG Performance Status (ECOG PS) of 0 to 2 Exclusion Criteria: Inflammatory breast cancer; bilateral disease (DCIS/LCIS in contralateral breast OK) 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 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 (defined as blood pressure > 160/90 mm Hg) 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 Known cataracts or retinopathy History of deep vein thrombosis (DVT)/pulmonary embolism (PE) Known activated protein C (APC) resistance, an inherited coagulation disorder Creatine clearance < 60 ml/min 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 Hormonal therapies including birth control and hormone replacement therapy during the study or within 1 week of registration; androgen therapy Allergy to endoxifen, goserelin, or exemestane or any of their components Participation in another investigational clinical trial ≤ 6 months of registration Known metastatic disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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 is a randomized 1:1 two-arm study with potential to switch to a single modified regimen based on Ki-67% at Week 4.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PK Cohort<br>(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<br>* (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).<br>* Other names: endoxifen;|
| Experimental: Treatment Cohort Arm 1 Initial Regimen<br>(Z)-endoxifen capsules orally once daily for 4 weeks. Dose will be based on the results of the 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. If Ki-67 > 10% at Week 4, participant will be offered modified regimen or be withdrawn and go on to surgery. | Drug: (Z)-endoxifen<br>* (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).<br>* Other names: endoxifen;|
| Active Comparator: Treatment Cohort Arm 2 Initial Regimen<br>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. If Ki-67 > 10% at Week 4, participant will be offered modified regimen or be withdrawn and go on to surgery. | Drug: exemestane<br>* exemestane tablets 25 mg<br>* Other names: Aromasin;Drug: goserelin<br>* goserelin 3.6 mg subcutaneous implant<br>* Other names: Zoladex;|
| Experimental: Treatment Cohort Arm 1 Modified Regimen<br>(Z)-endoxifen capsules orally once daily for 4 weeks + goserelin 3.6 mg by subcutaneous implant approximately every 28 days. (Z)-endoxifen dose will be based on the results of the PK Cohort. If Ki-67 ≤ 10% after 4 weeks of modified regimen, continue on this treatment for up to 6 total treatment cycles/Week 24. Each cycle is 28 days. If Ki-67 > 10% after 4 weeks of modified regimen, participant will be withdrawn and go on to surgery. | Drug: (Z)-endoxifen<br>* (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).<br>* Other names: endoxifen;Drug: goserelin<br>* goserelin 3.6 mg subcutaneous implant<br>* Other names: Zoladex;|
| Experimental: Treatment Cohort Arm 2 Modified Regimen<br>(Z)-endoxifen capsules orally once daily for 4 weeks + goserelin 3.6 mg by subcutaneous implant approximately every 28 days. (Z)-endoxifen dose will be based on the results of the PK Cohort. If Ki-67 ≤ 10% after 4 weeks of modified regimen, continue on this treatment for up to 6 total treatment cycles/Week 24. Each cycle is 28 days. If Ki-67 > 10% after 4 weeks of modified regimen, participant will be withdrawn and go on to surgery. | Drug: (Z)-endoxifen<br>* (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).<br>* Other names: endoxifen;Drug: goserelin<br>* goserelin 3.6 mg subcutaneous implant<br>* Other names: Zoladex;|
| Experimental: PK Cohort 80 mg<br>(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<br>* (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).<br>* Other names: endoxifen;|
| Experimental: PK Cohort 80 mg + OFS<br>(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<br>* (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).<br>* Other names: endoxifen;Drug: goserelin<br>* goserelin 3.6 mg subcutaneous implant<br>* Other names: Zoladex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Treatment 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 | After 4 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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) | up to 28 days | 
| PK Cohort - plasma (Z)-endoxifen concentration | Trough concentrations of (Z)-endoxifen for subjects in the Treatment Extension | 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 | Day 1 up to 12 weeks and up to end of treatment or up to 24 weeks. | 
| PK Cohort - Treatment 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 | After 4 weeks of treatment | 
| Both Cohorts - Incidence of Adverse Events assessed by CTCAE version 5.0 | Incidence and severity of adverse events per CTCAE by treatment | Informed consent up to follow up visit or up to 30 weeks | 
| Both Cohorts - Incidence of Serious Adverse Events assessed by CTCAE version 5.0 | Incidence of serious adverse events by treatment | Informed consent up to follow up visit or up to 30 weeks | 
| Both Cohorts - Incidence of Adverse Events Leading to Discontinuation | Incidence of adverse events leading to discontinuation by treatment | Informed consent up to up to end of treatment or up to 24 weeks | 
| Both Cohorts - Incidence of Dose Reductions | Proportion of patients who required a dose reduction by treatment arm | Day 1 up to time of surgery or up to 27 weeks | 
| Both Cohorts - Change in estradiol and estrone | Median percent change in the E1/E2 ratio | Day 1, up to 4 weeks, up to 12 weeks and up to end of treatment or up to 24 weeks. | 
| Both Cohorts - Percentage of subjects whose serum thymidine kinase 1 (TK1) falls below the detection limit after 4 weeks of treatment | 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 | Day 1, up to 4 weeks, up to 12 weeks and up to end of treatment or up to 24 weeks. | 
| Treatment Cohort - Radiographic Response Rate in the breast | Radiological response by RECIST 1.1 | Baseline Assessment up to 12 weeks and up to end of treatment or up to 24 weeks | 
| Treatment Cohort - 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 | At time of surgery or up to 27 weeks | 
| Treatment Cohort - Pre-Operative Endocrine Prognostic Index at time of surgery | Rate of Pre-Operative Endocrine Prognostic Index (PEPI) 0 at time of surgery using residual tumor specimen | At time of surgery or up to 27 weeks | 
| Treatment Cohort - Residual Cancer Burden at time of surgery | Rate of residual cancer burden class of 0-I at time of surgery | At time of surgery or up to 27 weeks | 
| Treatment Cohort - Conversion Rate | 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 | From baseline to time of surgery or up to 27 weeks | 
| Treatment Cohort - Actual Conversion Rate | 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) | At time of surgery or up to 27 weeks | 
| Treatment Cohort - Change in cholesterol levels | Change from pre-neoadjuvant treatment in cholesterol levels | Day 1 up to 4 weeks, up to 12 weeks and up to end of treatment or up to 24 weeks | 
| Treatment Cohort - Change in blood pressure | Change from pre-neoadjuvant treatment in blood pressure | Day 1 up to 4 weeks, up to 12 weeks and up to end of treatment or up to 24 weekss | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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