What is the mechanism of action of this treatment?

Common treatments for ER+/HER2- breast cancer, such as selective estrogen receptor modulators (SERMs) like (Z)-endoxifen, aromatase inhibitors, and ovarian suppression, work by targeting the hormonal pathways that fuel cancer growth. SERMs block estrogen receptors on cancer cells, preventing estrogen from promoting cell proliferation. Aromatase inhibitors reduce estrogen production in the body, lowering overall estrogen levels. Ovarian suppression stops the ovaries from producing estrogen. These mechanisms are crucial for patients to understand as they directly impact how effectively the treatments can inhibit cancer growth and help in personalizing therapy choices.

What side effects are associated with this type of intervention?

Common side effects of Selective Estrogen Receptor Modulators (SERMs) such as tamoxifen and (Z)-endoxifen include hot flashes, vaginal discharge or dryness, and an increased risk of blood clots. Aromatase inhibitors like exemestane can cause joint pain, bone thinning (osteoporosis), and cardiovascular issues. Both types of treatments may also lead to hair thinning and other mild forms of alopecia. It is important to discuss these potential side effects with your doctor to manage them effectively.

What prior FDA approvals exist?

The FDA has approved several Selective Estrogen Receptor Modulators (SERMs) for the treatment of breast cancer, similar to (Z)-endoxifen. Tamoxifen is one of the most well-known SERMs, approved for both the treatment and prevention of estrogen receptor-positive (ER+) breast cancer. Another SERM, raloxifene, is approved for the prevention of breast cancer in postmenopausal women. Additionally, aromatase inhibitors like exemestane, which decrease the amount of estrogen in the body, are also commonly used in the treatment of ER+ breast cancer. These treatments work by blocking estrogen from binding to cancer cells, thereby inhibiting tumor growth.

What other types of research exist?

Promising novel alternatives to (Z)-endoxifen for breast cancer patients in 2024 include: 1) Abemaciclib, a CDK4/6 inhibitor, which has shown efficacy in hormone receptor-positive breast cancer. 2) Tucatinib, a HER2-targeted therapy, especially for HER2-positive breast cancer with brain metastases. 3) PARP inhibitors like Olaparib for patients with BRCA mutations. 4) Immunotherapy agents such as Pembrolizumab for PD-L1 positive tumors. These alternatives offer different mechanisms of action and can be considered based on the specific characteristics of the breast cancer.

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Aromatase Inhibitor

Endoxifen for Breast Cancer (EVANGELINE Trial)

Phase 2

Recruiting

Led By Matthew P Goetz, MD

Research Sponsored by Atossa Therapeutics, Inc.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

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

Nottingham Grade 1 or 2

Must not have

Uncontrolled intercurrent illness including ongoing or active infection requiring systemic treatment with strong inhibitors/inducers of CYP450 enzymes, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled symptomatic cardiac arrhythmias, uncontrolled hypertension, uncontrolled diabetes, marked baseline prolongation of QT/QTc interval, known cataracts or retinopathy, history of deep vein thrombosis (DVT)/pulmonary embolism (PE), known activated protein C (APC) resistance, 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

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

Timeline

Screening 3 weeks

Treatment Varies

Follow Up day 1 up to 4 weeks, up to 12 weeks and up to end of treatment or up to 24 weeks

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing (Z)-endoxifen, a drug that blocks estrogen, in pre-menopausal women with a specific type of breast cancer. The study aims to see if this drug can slow down cancer growth by measuring a marker called Ki-67. Participants will take the drug daily for several months before surgery.

Who is the study for?

This trial is for premenopausal women over 18 with early-stage ER+/HER2- breast cancer. Participants must not be pregnant, lactating, or planning pregnancy within a year and agree to non-hormonal contraception. They should have an ECOG Performance Status of 0 to 2 and no prior breast cancer treatment or other active cancers in the last two years.

What is being tested?

(Z)-endoxifen, a drug that blocks estrogen from binding to cancer cells, is being tested against standard treatments exemestane and goserelin. The study has two parts: determining the proper dose of (Z)-endoxifen and comparing its effectiveness with standard treatments by measuring changes in a tumor marker after about four weeks.

What are the potential side effects?

(Z)-endoxifen may cause side effects similar to other SERMs like hot flashes, joint pain, mood swings, blood clots, vision changes due to cataracts or retinopathy. Exemestane can lead to bone loss or fractures; goserelin might cause symptoms related to low estrogen levels such as vaginal dryness.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My breast cancer is ER positive and HER2 negative, meeting specific test scores.

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My breast cancer is low or intermediate grade.

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My breast cancer is at stage IIA or IIB.

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My breast cancer is at stage T2 or T3 and has spread to nearby lymph nodes.

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I am a premenopausal woman aged 18 or older.

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My breast cancer is ER positive and HER2 negative, meeting specific test scores.

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I can take care of myself and am up and about more than half of my waking hours.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I do not have serious ongoing health issues that are not under control.

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I have not had breast cancer or any other cancer in the last 2 years.

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I am not on hormonal therapies, including birth control or hormone replacement, and won't be during the study.

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My cancer has spread to other parts of my body.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ day 1 up to 4 weeks, up to 12 weeks and up to end of treatment or up to 24 weeks

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~day 1 up to 4 weeks, up to 12 weeks and up to end of treatment or up to 24 weeks

This trial's timeline: 3 weeks for screening, Varies for treatment, and day 1 up to 4 weeks, up to 12 weeks and up to end of treatment or up to 24 weeks for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Plasma

Treatment Cohort - Endocrine sensitive disease rate based on Ki-67 percent after 4 weeks of treatment

Secondary study objectives

Both Cohorts - Change in estradiol and estrone

Both Cohorts - Incidence of Adverse Events Leading to Discontinuation

Both Cohorts - Incidence of Adverse Events assessed by CTCAE version 5.0

+23 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

7Treatment groups

Experimental Treatment

Active Control

Group I: Treatment Cohort Arm 2 Modified RegimenExperimental Treatment2 Interventions

(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.

Group II: Treatment Cohort Arm 1 Modified RegimenExperimental Treatment2 Interventions

Group III: Treatment Cohort Arm 1 Initial RegimenExperimental Treatment1 Intervention

(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.

Group IV: PK Cohort 80 mg + OFSExperimental Treatment2 Interventions

(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.

Group V: PK Cohort 80 mgExperimental Treatment1 Intervention

(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.

Group VI: PK CohortExperimental Treatment1 Intervention

(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.

Group VII: Treatment Cohort Arm 2 Initial RegimenActive Control2 Interventions

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

First Studied

Drug Approval Stage

How many patients have taken this drug

goserelin

1999

Completed Phase 3

~5440

0 / 11Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for ER+/HER2- breast cancer, such as selective estrogen receptor modulators (SERMs) like (Z)-endoxifen, aromatase inhibitors, and ovarian suppression, work by targeting the hormonal pathways that fuel cancer growth. SERMs block estrogen receptors on cancer cells, preventing estrogen from promoting cell proliferation. Aromatase inhibitors reduce estrogen production in the body, lowering overall estrogen levels. Ovarian suppression stops the ovaries from producing estrogen. These mechanisms are crucial for patients to understand as they directly impact how effectively the treatments can inhibit cancer growth and help in personalizing therapy choices.