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

• ClinicalTrials.gov Identifier: NCT05607004
• Recruitment Status: Recruiting
• First Posted: November 7, 2022
• Last Update Posted: January 31, 2023
• Sponsor: Atossa Therapeutics, Inc.
• Collaborator: InClin
• Information provided by (Responsible Party): Atossa Therapeutics, Inc.

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. 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 taking a biopsy after 4 weeks of treatment to measure Ki-67. Ki-67 is a cancer marker that indicates how well the treatments work to slow cancer cell growth. Overall, this study will help determine if (Z)-endoxifen can effectively treat premenopausal women with ER+/HER2- breast cancer without the need for monthly injections of goserelin which is a medication given to block the ovaries from making estrogen (also called ovarian suppression). Studies have shown harmful long-term effects of ovarian suppression in premenopausal women.

The PK part of the study will be enrolled first, enrolling about 6 study participants who will all receive oral once daily (Z)-endoxifen treatment. 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.

Condition or disease	Intervention/treatment	Phase
Breast Neoplasms; Invasive Breast Cancer; Estrogen-receptor-positive Breast Cancer; HER2-negative Breast Cancer	Drug: Z-endoxifen; Drug: exemestane; Drug: goserelin	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 174 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

This multicenter open-label study consists of two cohorts: PK and Treatment

The PK Cohort is a single-arm 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)
• Primary Purpose: Treatment
• 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
• Estimated Study Start Date: January 2023
• Estimated Primary Completion Date: January 2025
• Estimated Study Completion Date: July 2025

Arms and Interventions

Arm	Intervention/treatment
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 up to 6 cycles/Week 24 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 Name: endoxifen
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 Name: 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 once monthly. 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 Name: Aromasin; Drug: goserelin; goserelin 3.6 mg subcutaneous implant; Other Name: Zoladex
Experimental: Treatment Cohort Arm 1 Modified Regimen; (Z)-endoxifen capsules orally once daily for 4 weeks + goserelin 3.6 mg by subcutaneous implant once monthly. (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; (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 Name: endoxifen; Drug: goserelin; goserelin 3.6 mg subcutaneous implant; Other Name: Zoladex
Experimental: Treatment Cohort Arm 2 Modified Regimen; (Z)-endoxifen capsules orally once daily for 4 weeks + goserelin 3.6 mg by subcutaneous implant once monthly. (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; (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 Name: endoxifen; Drug: goserelin; goserelin 3.6 mg subcutaneous implant; Other Name: Zoladex

Outcome Measures

Primary Outcome Measures :

1. PK Cohort - (Z)-endoxifen steady-state plasma concentrations [ Time Frame: After 4 weeks of treatment ]
   (Z)-endoxifen steady-state plasma concentrations (Css) of eligible subjects who completed at least one cycle of treatment (28 +/- 3 days)
2. Treatment Cohort - Endocrine sensitive disease rate based on Ki-67 percent after 4 weeks of treatment [ Time Frame: 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 (or if both breasts are involved, both breast tumor biopsies find Ki-67 less than or equal to 10 percent) among subjects who began protocol treatment

Secondary Outcome Measures :

1. PK Cohort - Area under the plasma (Z)-endoxifen concentration-time curve from time zero to last measurable concentration [ Time Frame: 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 eligible subjects who completed at least one cycle of treatment (28 +/- 3 days)
2. PK Cohort - Area under the plasma (E)-endoxifen concentration-time curve from time zero to last measurable concentration [ Time Frame: 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 eligible subjects who completed at least one cycle of treatment (28 +/- 3 days)
3. PK Cohort - Accumulation and accumulation half-life [ Time Frame: Days 1 and 28 ]
   Accumulation and accumulation half-life (Day 28 AUC0-24/Day 1 AUC0-24) of eligible subjects who completed at least one cycle of treatment (28 +/- 3 days)
4. PK Cohort - (Z)-endoxifen steady-state clearance [ Time Frame: up to 28 days ]
   (Z)-endoxifen CLss (steady-state clearance) of eligible subjects who completed at least one cycle of treatment (28 +/- 3 days)
5. PK Cohort - (E)-endoxifen steady-state clearance [ Time Frame: up to 28 days ]
   (E)-endoxifen CLss (steady-state clearance) of eligible subjects who completed at least one cycle of treatment (28 +/- 3 days)
6. PK Cohort - Maximum plasma (Z)-endoxifen concentration [ Time Frame: up to 28 days ]
   Maximum plasma (Z)-endoxifen concentration (Cmax) of eligible subjects who completed at least one cycle of treatment (28 +/- 3 days)
7. PK Cohort - Maximum plasma (E)-endoxifen concentration [ Time Frame: up to 28 days ]
   Maximum plasma (E)-endoxifen concentration (Cmax) of eligible subjects who completed at least one cycle of treatment (28 +/- 3 days)
8. PK Cohort - Time to plasma (Z)-endoxifen maximum concentration [ Time Frame: up to 28 days ]
   Time to plasma (Z)-endoxifen maximum concentration (Tmax) of eligible subjects who completed at least one cycle of treatment (28 +/- 3 days)
9. PK Cohort - Time to plasma (E)-endoxifen maximum concentration [ Time Frame: up to 28 days ]
   Time to plasma (E)-endoxifen maximum concentration (Tmax) of eligible subjects who completed at least one cycle of treatment (28 +/- 3 days)
10. PK Cohort - Treatment Cohort - Endocrine sensitive disease rate based on Ki-67 percent after 4 weeks of treatment [ Time Frame: 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 (or if both breasts are involved, both breast tumor biopsies find Ki-67 less than or equal to 10 percent) among subjects who began protocol treatment
11. Both Cohorts - Incidence of Adverse Events assessed by CTCAE version 5.0 [ Time Frame: Day 1 up to post-surgery follow up visit or up to 28 weeks ]
    Incidence and severity of adverse events per CTCAE by treatment
12. Both Cohorts - Incidence of Serious Adverse Events assessed by CTCAE version 5.0 [ Time Frame: Day 1 up to post-surgery follow up visit or up to 28 weeks ]
    Incidence of serious adverse events by treatment
13. Both Cohorts - Incidence of Adverse Events Leading to Discontinuation [ Time Frame: Day 1 up to post-surgery follow up visit or up to 28 weeks ]
    Incidence of adverse events leading to discontinuation by treatment
14. Both Cohorts - Percentage of subjects whose serum thymidine kinase 1 (TK1) falls below the detection limit after 4 weeks of treatment [ Time Frame: 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
15. Treatment Cohort - Overall Response Rate according to World Health Organization Criteria assessed by MRI at Week 12 [ Time Frame: Baseline Assessment up to Cycle 3 (each cycle is 28 days) or up to 12 weeks ]
    Radiological response (by World Health Organization [WHO] Criteria for Clinical Response) rates at 12 weeks assessed by MRI
16. Treatment Cohort - Overall Response Rate according to World Health Organization Criteria assessed by MRI at Week 24 [ Time Frame: Baseline Assessment up to end of treatment visit or up to 24 weeks ]
    Radiological response (by World Health Organization [WHO] Criteria for Clinical Response) rates at 24 weeks assessed by MRI
17. Treatment Cohort - Pathologic Complete Response per American Joint Committee on Cancer staging system at time of surgery [ Time Frame: At time of surgery or up to 25 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 lymph nodes removed following completion of neoadjuvant systemic therapy
18. Treatment Cohort - Rate of Pre-Operative Endocrine Prognostic Index at time of surgery [ Time Frame: At time of surgery or up to 25 weeks ]
    Rate of Pre-Operative Endocrine Prognostic Index (PEPI) 0 at time of surgery using residual tumor specimen
19. Treatment Cohort - Class of Residual Cancer Burden at time of surgery [ Time Frame: At time of surgery or up to 25 weeks ]
    Residual cancer burden class of II-III rate at time of surgery
20. Treatment Cohort - Conversion Rate [ Time Frame: From baseline to time of surgery or up to 25 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
21. Treatment Cohort - Actual Conversion Rate [ Time Frame: At time of surgery or up to 25 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)
22. Treatment Cohort - Change from pre-neoadjuvant treatment in estrone (E1)/estradiol(E2) [ Time Frame: Day 1 up to end of treatment visit or up to 24 weeks ]
    Change from pre-neoadjuvant treatment in estrone (E1)/estradiol(E2)
23. Treatment Cohort - Change from pre-neoadjuvant treatment in cholesterol levels [ Time Frame: Day 1 up to end of treatment visit or up to 24 weeks ]
    Change from pre-neoadjuvant treatment in cholesterol levels

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Premenopausal women 18 years or older
• Not lactating, pregnant, or planning to become pregnant in the next year
• Agree to use 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 Stage IIA or IIB invasive breast cancer (per American Joint Committee on Cancer [AJCC] 8th edition clinical staging)
• Nottingham Grade 1 or 2
• Largest tumor diameter > 2.0 cm either by imaging or clinical examination
• ECOG Performance Status (ECOG PS) of 0 to 2

Exclusion Criteria:

• Inflammatory breast cancer
• 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] >50 mmol/mol)
• 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/hr by the Cockcroft-Gault equation
• 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
• Allergy to endoxifen, goserelin, or exemestane or any of their components
• Participation in another investigational clinical trial ≤ 6 months of registration

Contacts and Locations

Contacts

Contact: Heather Fraser, Ph D; 206-707-3088; heather.fraser@atossainc.com

Contact: Melinda M. Bomar; melinda.bomar@atossainc.com

Locations

United States, Arizona

Mayo Clinic Arizona; Recruiting

Phoenix, Arizona, United States, 85054

Contact: Alicia Van Stone 480-574-2802 VanStone.Alicia@mayo.edu

Principal Investigator: Lida Mina, MD

United States, Florida

Mayo Clinic Florida; Recruiting

Jacksonville, Florida, United States, 32224

Contact: Megan Skoglund 904-953-2451 skoglund.megan@mayo.edu

Principal Investigator: Pooja Advani, MD

United States, Minnesota

Mayo Clinic Rochester; Recruiting

Rochester, Minnesota, United States, 55905

Contact: Sarah Cable 507-266-0539 Cable.Sarah@mayo.edu

Principal Investigator: Matthew Goetz, MD

United States, Texas

Tranquil Clinical Research; Recruiting

Webster, Texas, United States, 77598

Contact: Amber Christian 713-907-6054 amberc@tranquilityresearch.com

Principal Investigator: John G Knecht, M.D.

Sponsors and Collaborators

Atossa Therapeutics, Inc.

InClin

Investigators

• Principal Investigator: Matthew P Goetz, MD; Mayo Clinic

More Information

• Responsible Party: Atossa Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT05607004
• Other Study ID Numbers: ATOS-Z-201
• First Posted: November 7, 2022
• Last Update Posted: January 31, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Atossa Therapeutics, Inc.:

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

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Exemestane; Goserelin; Antineoplastic Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal