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Trial record 1 of 1 for:    ATOS-Z-201
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(Z)-Endoxifen for the Treatment of Premenopausal Women With ER+/HER2- Breast Cancer (EVANGELINE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05607004
Recruitment Status : Recruiting
First Posted : November 7, 2022
Last Update Posted : January 31, 2023
Sponsor:
Collaborator:
InClin
Information provided by (Responsible Party):
Atossa Therapeutics, Inc.

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

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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

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

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




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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05607004


Contacts
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Contact: Heather Fraser, Ph D 206-707-3088 heather.fraser@atossainc.com
Contact: Melinda M. Bomar melinda.bomar@atossainc.com

Locations
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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
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Principal Investigator: Matthew P Goetz, MD Mayo Clinic
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Responsible Party: Atossa Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT05607004    
Other Study ID Numbers: ATOS-Z-201
First Posted: November 7, 2022    Key Record Dates
Last Update Posted: January 31, 2023
Last Verified: January 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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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