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

Atossa Therapeutics

Status and phase: Enrolling; Phase 2

Conditions: Estrogen-receptor-positive Breast Cancer; Breast Neoplasms; HER2-negative Breast Cancer; Invasive Breast Cancer

Treatments: Drug: exemestane; Drug: goserelin; Drug: (Z)-endoxifen

Study type: Interventional

Funder types: Industry; Other

Identifiers

NCT05607004

ATOS-Z-201

Details and patient eligibility

About

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.

Enrollment: 180 estimated patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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180 participants in 7 patient groups

PK Cohort

Experimental group

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.

Treatment:

Drug: (Z)-endoxifen

Treatment Cohort Arm 1 Initial Regimen

Experimental group

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.

Treatment:

Drug: (Z)-endoxifen

Treatment Cohort Arm 2 Initial Regimen

Active Comparator group

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.

Treatment:

Drug: goserelin

Drug: exemestane

Treatment Cohort Arm 1 Modified Regimen

Experimental group

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.

Treatment:

Drug: (Z)-endoxifen

Drug: goserelin

Treatment Cohort Arm 2 Modified Regimen

Experimental group

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.

Treatment:

Drug: (Z)-endoxifen

Drug: goserelin

PK Cohort 80 mg

Experimental group

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.

Treatment:

Drug: (Z)-endoxifen

PK Cohort 80 mg + OFS

Experimental group

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.

Treatment:

Drug: (Z)-endoxifen

Drug: goserelin