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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Breast Neoplasms; Invasive Breast Cancer; HER2-negative Breast Cancer; Estrogen-receptor-positive Breast Cancer
• Intervention / Treatment: Drug: exemestane; Drug: goserelin; Drug: (Z)-endoxifen

• Study Type: Interventional
• Enrollment (Estimated): 180
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Arezoo Mirad, MD, MS; Phone Number: 650-647-4913; Email: Arezoo.Mirad@Atossainc.com

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Recruiting
      • Mayo Clinic Arizona
      • Principal Investigator: Lida Mina, MD
    • Tucson, Arizona, United States, 85719
      • Recruiting
      • University of Arizona
      • Principal Investigator: Sima Ehsani, MD
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Recruiting
      • Mayo Clinic Florida
      • Principal Investigator: Pooja Advani, MD
  • Kentucky
    • Edgewood, Kentucky, United States, 41017
      • Recruiting
      • St. Elizabeth Healthcare
      • Principal Investigator: Daniel Flora, MD
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic Rochester
      • Principal Investigator: Matthew Goetz, MD
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine
      • Principal Investigator: Nusayba Bagegni, MD
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • Recruiting
      • Avera Cancer Institute
      • Principal Investigator: Jason Jones, MD
  • Texas
    • Webster, Texas, United States, 77598
      • Withdrawn
      • Tranquility Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Cohort Arm 1 Initial Regimen; (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; (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).; Other Names: endoxifen
Experimental: PK Cohort; (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; (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).; Other Names: endoxifen
Active Comparator: Treatment Cohort Arm 2 Initial Regimen; 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; exemestane tablets 25 mg; Other Names: Aromasin; Drug: goserelin; goserelin 3.6 mg subcutaneous implant; Other Names: Zoladex
Experimental: Treatment Cohort Arm 1 Modified Regimen; (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: goserelin; goserelin 3.6 mg subcutaneous implant; Other Names: Zoladex; Drug: (Z)-endoxifen; (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).; Other Names: endoxifen
Experimental: Treatment Cohort Arm 2 Modified Regimen; (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: goserelin; goserelin 3.6 mg subcutaneous implant; Other Names: Zoladex; Drug: (Z)-endoxifen; (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).; Other Names: endoxifen
Experimental: PK Cohort 80 mg; (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; (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).; Other Names: endoxifen
Experimental: PK Cohort 80 mg + OFS; (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: goserelin; goserelin 3.6 mg subcutaneous implant; Other Names: Zoladex; Drug: (Z)-endoxifen; (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).; Other Names: endoxifen

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Atossa Therapeutics, Inc.
• Collaborators: InClin
• Investigators: Principal Investigator: Matthew P Goetz, MD, Mayo Clinic

Study record dates

Study Major Dates

• Study Start (Actual): February 14, 2023
• Primary Completion (Estimated): February 1, 2026
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: October 26, 2022
• First Submitted That Met QC Criteria: October 31, 2022
• First Posted (Actual): November 7, 2022

Study Record Updates

• Last Update Posted (Estimated): April 26, 2024
• Last Update Submitted That Met QC Criteria: April 25, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: breast cancer; neoadjuvant; tamoxifen; Stage II; Ki-67; human epidermal growth factor receptor 2 negative; ER+/HER2-; endocrine therapy; (Z)-endoxifen; exemestane; goserelin; estrogen receptor negative; PKCB1
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Goserelin; Exemestane
• Other Study ID Numbers: ATOS-Z-201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No