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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT05607004
Other study ID # ATOS-Z-201
Secondary ID
Status Recruiting
Phase Phase 2
First received
Last updated
Start date February 14, 2023
Est. completion date September 2026

Study information

Verified date April 2024
Source Atossa Therapeutics, Inc.
Contact Arezoo Mirad, MD, MS
Phone 650-647-4913
Email Arezoo.Mirad@Atossainc.com
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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. (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.


Recruitment information / eligibility

Status Recruiting
Enrollment 180
Est. completion date September 2026
Est. primary completion date February 2026
Accepts healthy volunteers No
Gender Female
Age group 18 Years and older
Eligibility 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 Design


Intervention

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).
exemestane
exemestane tablets 25 mg
goserelin
goserelin 3.6 mg subcutaneous implant

Locations

Country Name City State
United States St. Elizabeth Healthcare Edgewood Kentucky
United States Mayo Clinic Florida Jacksonville Florida
United States Mayo Clinic Arizona Phoenix Arizona
United States Mayo Clinic Rochester Rochester Minnesota
United States Washington University School of Medicine Saint Louis Missouri
United States Avera Cancer Institute Sioux Falls South Dakota
United States University of Arizona Tucson Arizona
United States Tranquility Research Webster Texas

Sponsors (2)

Lead Sponsor Collaborator
Atossa Therapeutics, Inc. InClin

Country where clinical trial is conducted

United States, 

Outcome

Type Measure Description Time frame Safety issue
Primary 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
Primary 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 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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.
Secondary 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.
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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.
Secondary 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.
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
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