A Phase 2 Trial of (Z)-Endoxifen + Goserelin as Neoadjuvant Treatment for Premenopausal Women With ER+, HER2-, Breast Cancer
Summary
This open-label research study is studying (Z)-endoxifen as a possible treatment for pre-menopausal women with ER+/HER2- breast cancer. (Z)-endoxifen belongs to a group of drugs called selective estrogen receptor modulators or "SERM", which help block estrogen from attaching to cancer cells. This study has two parts: a pharmacokinetic part and a treatment part. The PK part (how the body processes the drug) will enroll about 18 participants. All participants will take (Z)-endoxifen capsules daily. Twelve participants will be randomly assigned (50/50 chance) to take (Z)-endoxifen alone or (Z)-endoxifen with a monthly injection of goserelin a drug that temporarily stops the ovaries from making estrogen. This part will help determine the best dose of (Z)-endoxifen by measuring the drug levels in the blood and how long the body takes to remove it. The Treatment Cohort has been simplified to a single study arm (Z)-endoxifen + goserelin. Up to 20 participants will be enrolled that have a baseline Ki-67 ≤ 10% and 45 participants will be enrolled that have a baseline Ki-67\>10%. A key goal of the study is to see if (Z)-endoxifen can slow down or stop tumor growth as measured by a reduction in Ki-67 levels. Tumor tissue samples will be taken by breast biopsy after about 4 weeks of treatment to check levels of this biomarker. If the tumor shows signs of response, participants can continue treatment for up to 24 weeks or until they have surgery. Study participation is up to 6 months (24 weeks of treatment) followed by surgery and a one-month follow up visit.
Arms & interventions
- 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).
- Druggoserelin
goserelin 3.6 mg subcutaneous implant
Outcome measures
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)
Time frame: After 4 weeks of treatment
For Analysis of Cohort A (Treatment Cohort): determine whether the week 4 Ki-67≤10% rate is at least 65%
For analysis Cohort A (subjects that have a baseline Ki-67\>10%): the primary objective is to determine whether the Week 4 Ki-67 ≤ 10% rate is at least 65% among premenopausal women with primary estrogen receptor positive (ER+), Human Epidermal Growth Factor Receptor 2 negative (HER2-) breast cancer.
Time frame: After 4 weeks of treatment
For analysis Cohort B (Treatment Cohort): determine the objective tumor response rate at 24 weeks
For analysis Cohort B (subjects have baseline Ki-67≤ 10%): the primary objective is to determine the objective tumor response rate at 24 weeks among premenopausal women with ER+, HER2-, Ki-67 ≤ 10% breast cancer receiving (Z) endoxifen plus goserelin.
Time frame: After 24 weeks of treatment
Secondary
PK Cohort - Area under the plasma (Z)-endoxifen concentration-time curve from time zero to last measurable concentration
Time frame: Days 1 and 28
PK Cohort - Area under the plasma (E)-endoxifen concentration-time curve from time zero to last measurable concentration
Time frame: Days 1 and 28
PK Cohort - Accumulation and accumulation half-life
Time frame: Days 1 and 28
PK Cohort - (Z)-endoxifen steady-state clearance
Time frame: up to 28 days
PK Cohort - (E)-endoxifen steady-state clearance
Time frame: up to 28 days
PK Cohort - Maximum plasma (Z)-endoxifen concentration
Time frame: up to 28 days
PK Cohort - Maximum plasma (E)-endoxifen concentration
Time frame: up to 28 days
PK Cohort - Time to plasma (Z)-endoxifen maximum concentration
Time frame: up to 28 days
PK Cohort - Time to plasma (E)-endoxifen maximum concentration
Time frame: up to 28 days
PK Cohort - plasma (Z)-endoxifen concentration
Time frame: Day 1 up to 12 weeks and up to end of treatment or up to 24 weeks.
PK Cohort - plasma (E)-endoxifen concentration
Time frame: Day 1 up to 12 weeks and up to end of treatment or up to 24 weeks.
PK Cohort- Endocrine sensitive disease rate based on Ki-67 percent after 4 weeks of treatment
Time frame: After 4 weeks of treatment
All Cohorts - Incidence and severity of adverse events per CTCAE by treatment
Time frame: Informed consent up to follow up visit or up to 30 weeks
All Cohorts - Incidence of Serious Adverse Events assessed by CTCAE version 5.0
Time frame: Informed consent up to follow up visit or up to 30 weeks
All Cohorts - Incidence of Dose Reductions
Time frame: Informed consent up to end of treatment or up to 24 weeks
All Cohorts - Change in estradiol and estrone
Time frame: Day 1, up to 4 weeks and up to end of treatment or up to 24 weeks.
All Cohorts - Percentage of subjects whose serum thymidine kinase 1 (TK1) is not detectable at 4 weeks and 24 weeks.
Time frame: Day 1, up to 4 weeks and up to end of treatment or up to 24 weeks.
Treatment Cohorts - Assess additional PK parameters of (Z)-endoxifen and (E)-endoxifen
Time frame: Day 1, up to 4 weeks, up to 12 weeks and up to 24 weeks
Treatment Cohorts - Radiographic Response Rate in the breast
Time frame: Baseline Assessment, up to 4 weeks, up to 12 weeks, and up to 24 weeks
Treatment Cohorts - Pathologic Complete Response per American Joint Committee on Cancer staging system at time of surgery
Time frame: At time of surgery or up to 27 weeks
Treatment Cohorts - Pre-Operative Endocrine Prognostic Index at time of surgery
Time frame: At time of surgery or up to 27 weeks
Treatment Cohorts - Residual Cancer Burden at time of surgery
Time frame: At time of surgery or up to 27 weeks
Treatment Cohorts - Conversion Rate
Time frame: From baseline to time of surgery or up to 27 weeks
Treatment Cohorts - Actual Conversion Rate
Time frame: At time of surgery or up to 27 weeks
Treatment Cohorts - Change in menopause quality of life (MENQOL)
Time frame: baseline, up to 4 weeks, and up to 24 weeks
Treatment Cohorts - Nodal response rate
Time frame: At time of surgery or up to 27 weeks
Eligibility criteria
Study locations (15)
Mayo Clinic Arizona
Phoenix, Arizona, 85054
University of Arizona
Tucson, Arizona, 85719
California Research Institute
Los Angeles, California, 90027
Mayo Clinic Florida
Jacksonville, Florida, 32224
Northwestern University
Chicago, Illinois, 60611
St. Elizabeth Healthcare
Edgewood, Kentucky, 41017
Henry Ford Cancer Institute
Detroit, Michigan, 48202
Mayo Clinic Rochester
Rochester, Minnesota, 55905
Washington University School of Medicine
St Louis, Missouri, 63110
Avera Cancer Institute
Sioux Falls, South Dakota, 57105
Vanderbilt Ingram Cancer Center
Nashville, Tennessee, 37204
Baylor University
Houston, Texas, 77054
Tranquility Research
Webster, Texas, 77598
Bon Secours Cancer Institute
Midlothian, Virginia, 23114
Fred Hutchinson Cancer Center
Seattle, Washington, 98109