Back to results(Z)-Endoxifen for the Treatment of Premenopausal Women With ER+/HER2- Breast Cancer (EVANGELINE)
Primary Purpose
Breast Neoplasms, Invasive Breast Cancer, Estrogen-receptor-positive Breast Cancer
Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
(Z)-endoxifen
exemestane
goserelin
Sponsored by
About this trial
This is an interventional treatment trial for Breast Neoplasms focused on measuring 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
Eligibility Criteria
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
Sites / Locations
- Mayo Clinic ArizonaRecruiting
- Mayo Clinic FloridaRecruiting
- St. Elizabeth HealthcareRecruiting
- Mayo Clinic RochesterRecruiting
- Washington University School of MedicineRecruiting
- Tranquil Clinical ResearchRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm 7
Arm Type
Experimental
Experimental
Active Comparator
Experimental
Experimental
Experimental
Experimental
Arm Label
PK Cohort
Treatment Cohort Arm 1 Initial Regimen
Treatment Cohort Arm 2 Initial Regimen
Treatment Cohort Arm 1 Modified Regimen
Treatment Cohort Arm 2 Modified Regimen
PK Cohort 80 mg
PK Cohort 80 mg + OFS
Arm Description
(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.
(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.
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.
(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.
(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.
(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.
(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.
Outcomes
Primary Outcome Measures
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)
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
Secondary Outcome Measures
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)
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)
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)
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)
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)
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)
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)
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)
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)
PK Cohort - plasma (Z)-endoxifen concentration
Trough concentrations of (Z)-endoxifen for subjects in the Treatment Extension
PK Cohort - plasma (E)-endoxifen concentration
Trough concentrations of (Z)-endoxifen for subjects in the Treatment Extension
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
Both Cohorts - Incidence of Adverse Events assessed by CTCAE version 5.0
Incidence and severity of adverse events per CTCAE by treatment
Both Cohorts - Incidence of Serious Adverse Events assessed by CTCAE version 5.0
Incidence of serious adverse events by treatment
Both Cohorts - Incidence of Adverse Events Leading to Discontinuation
Incidence of adverse events leading to discontinuation by treatment
Both Cohorts - Incidence of Dose Reductions
Proportion of patients who required a dose reduction by treatment arm
Both Cohorts - Change in estradiol and estrone
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
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
Treatment Cohort - Radiographic Response Rate in the breast
Radiological response by RECIST 1.1
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
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
Treatment Cohort - Residual Cancer Burden at time of surgery
Rate of residual cancer burden class of 0-I at time of surgery
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
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)
Treatment Cohort - Change in cholesterol levels
Change from pre-neoadjuvant treatment in cholesterol levels
Treatment Cohort - Change in blood pressure
Change from pre-neoadjuvant treatment in blood pressure
Full Information
NCT ID
NCT05607004
First Posted
October 26, 2022
Last Updated
October 18, 2023
Sponsor
Atossa Therapeutics, Inc.
Collaborators
InClin
1. Study Identification
Unique Protocol Identification Number
NCT05607004
Brief Title
(Z)-Endoxifen for the Treatment of Premenopausal Women With ER+/HER2- Breast Cancer
Acronym
EVANGELINE
Official Title
A Randomized Phase 2 Non-inferiority Trial of (Z)-Endoxifen and Exemestane + Goserelin as Neoadjuvant Treatment in Premenopausal Women With ER+/HER2- Breast Cancer
Study Type
Interventional
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 14, 2023 (Actual)
Primary Completion Date
February 2026 (Anticipated)
Study Completion Date
September 2026 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Atossa Therapeutics, Inc.
Collaborators
InClin
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
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)
Allocation
Randomized
Enrollment
180 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
PK Cohort
Arm Type
Experimental
Arm Description
(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.
Arm Title
Treatment Cohort Arm 1 Initial Regimen
Arm Type
Experimental
Arm Description
(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.
Arm Title
Treatment Cohort Arm 2 Initial Regimen
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Treatment Cohort Arm 1 Modified Regimen
Arm Type
Experimental
Arm Description
(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.
Arm Title
Treatment Cohort Arm 2 Modified Regimen
Arm Type
Experimental
Arm Description
(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.
Arm Title
PK Cohort 80 mg
Arm Type
Experimental
Arm Description
(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.
Arm Title
PK Cohort 80 mg + OFS
Arm Type
Experimental
Arm Description
(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.
Intervention Type
Drug
Intervention Name(s)
(Z)-endoxifen
Other Intervention Name(s)
endoxifen
Intervention Description
(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).
Intervention Type
Drug
Intervention Name(s)
exemestane
Other Intervention Name(s)
Aromasin
Intervention Description
exemestane tablets 25 mg
Intervention Type
Drug
Intervention Name(s)
goserelin
Other Intervention Name(s)
Zoladex
Intervention Description
goserelin 3.6 mg subcutaneous implant
Primary Outcome Measure Information:
Title
PK Cohort - (Z)-endoxifen steady-state plasma concentrations
Description
(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
Title
Treatment Cohort - Endocrine sensitive disease rate based on Ki-67 percent after 4 weeks of treatment
Description
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
Secondary Outcome Measure Information:
Title
PK Cohort - Area under the plasma (Z)-endoxifen concentration-time curve from time zero to last measurable concentration
Description
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
Title
PK Cohort - Area under the plasma (E)-endoxifen concentration-time curve from time zero to last measurable concentration
Description
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
Title
PK Cohort - Accumulation and accumulation half-life
Description
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
Title
PK Cohort - (Z)-endoxifen steady-state clearance
Description
(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
Title
PK Cohort - (E)-endoxifen steady-state clearance
Description
(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
Title
PK Cohort - Maximum plasma (Z)-endoxifen concentration
Description
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
Title
PK Cohort - Maximum plasma (E)-endoxifen concentration
Description
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
Title
PK Cohort - Time to plasma (Z)-endoxifen maximum concentration
Description
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
Title
PK Cohort - Time to plasma (E)-endoxifen maximum concentration
Description
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
Title
PK Cohort - plasma (Z)-endoxifen concentration
Description
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.
Title
PK Cohort - plasma (E)-endoxifen concentration
Description
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.
Title
PK Cohort - Treatment Cohort - Endocrine sensitive disease rate based on Ki-67 percent after 4 weeks of treatment
Description
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
Title
Both Cohorts - Incidence of Adverse Events assessed by CTCAE version 5.0
Description
Incidence and severity of adverse events per CTCAE by treatment
Time Frame
Informed consent up to follow up visit or up to 30 weeks
Title
Both Cohorts - Incidence of Serious Adverse Events assessed by CTCAE version 5.0
Description
Incidence of serious adverse events by treatment
Time Frame
Informed consent up to follow up visit or up to 30 weeks
Title
Both Cohorts - Incidence of Adverse Events Leading to Discontinuation
Description
Incidence of adverse events leading to discontinuation by treatment
Time Frame
Informed consent up to up to end of treatment or up to 24 weeks
Title
Both Cohorts - Incidence of Dose Reductions
Description
Proportion of patients who required a dose reduction by treatment arm
Time Frame
Day 1 up to time of surgery or up to 27 weeks
Title
Both Cohorts - Change in estradiol and estrone
Description
Median percent change in the E1/E2 ratio
Time Frame
Day 1, up to 4 weeks, up to 12 weeks and up to end of treatment or up to 24 weeks.
Title
Both Cohorts - Percentage of subjects whose serum thymidine kinase 1 (TK1) falls below the detection limit after 4 weeks of treatment
Description
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
Time Frame
Day 1, up to 4 weeks, up to 12 weeks and up to end of treatment or up to 24 weeks.
Title
Treatment Cohort - Radiographic Response Rate in the breast
Description
Radiological response by RECIST 1.1
Time Frame
Baseline Assessment up to 12 weeks and up to end of treatment or up to 24 weeks
Title
Treatment Cohort - Pathologic Complete Response per American Joint Committee on Cancer staging system at time of surgery
Description
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
Time Frame
At time of surgery or up to 27 weeks
Title
Treatment Cohort - Pre-Operative Endocrine Prognostic Index at time of surgery
Description
Rate of Pre-Operative Endocrine Prognostic Index (PEPI) 0 at time of surgery using residual tumor specimen
Time Frame
At time of surgery or up to 27 weeks
Title
Treatment Cohort - Residual Cancer Burden at time of surgery
Description
Rate of residual cancer burden class of 0-I at time of surgery
Time Frame
At time of surgery or up to 27 weeks
Title
Treatment Cohort - Conversion Rate
Description
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
Time Frame
From baseline to time of surgery or up to 27 weeks
Title
Treatment Cohort - Actual Conversion Rate
Description
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)
Time Frame
At time of surgery or up to 27 weeks
Title
Treatment Cohort - Change in cholesterol levels
Description
Change from pre-neoadjuvant treatment in cholesterol levels
Time Frame
Day 1 up to 4 weeks, up to 12 weeks and up to end of treatment or up to 24 weeks
Title
Treatment Cohort - Change in blood pressure
Description
Change from pre-neoadjuvant treatment in blood pressure
Time Frame
Day 1 up to 4 weeks, up to 12 weeks and up to end of treatment or up to 24 weekss
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Heather Fraser, Ph D
Phone
206-707-3088
Email
heather.fraser@atossainc.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Matthew P Goetz, MD
Organizational Affiliation
Mayo Clinic
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic Arizona
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85054
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lida Mina, MD
Facility Name
Mayo Clinic Florida
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Pooja Advani, MD
Facility Name
St. Elizabeth Healthcare
City
Edgewood
State/Province
Kentucky
ZIP/Postal Code
41017
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Daniel Flora, MD
Facility Name
Mayo Clinic Rochester
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Matthew Goetz, MD
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nusayba Bagegni, MD
Facility Name
Tranquil Clinical Research
City
Webster
State/Province
Texas
ZIP/Postal Code
77598
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
John G Knecht, M.D.
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
(Z)-Endoxifen for the Treatment of Premenopausal Women With ER+/HER2- Breast Cancer
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