A Phase 2 Trial of (Z)-Endoxifen + Goserelin as Neoadjuvant Treatment for Premenopausal Women With ER+, HER2-, Breast Cancer
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 87
- 试验地点
- 25
- 主要终点
- PK Cohort - (Z)-endoxifen steady-state plasma concentrations
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Female sex assigned at birth. Female to male transgender individuals who have not had any hormonal therapy may be considered for the trial after review and approval from the medical monitor and study sponsor.
- •Age 18 years or older
- •Not lactating, pregnant, or planning to become pregnant in the next year and agrees to take adequate steps to prevent becoming pregnant beginning at informed consent, during treatment and for 9 months after last dose and agree to not breast feed during treatment and for 3 months after last dose.
- •Must agree to use at least one non-hormonal highly effective method of contraception for the entire duration of study participation beginning at informed consent. Highly effective methods of birth control are defined as those, alone or in combination, that resulted in a low failure rate of <1% per year when used consistently and correctly such as intrauterine devices (IUDs, non-hormonal such as copper IUD), bilateral tubal occlusion, sexual abstinence or vasectomized partner
- •Premenopausal defined as any female who:
- •is menstruating or
- •is not menstruating (last menstrual period > 3 months prior to registration) but has a plasma estradiol in the premenopausal range as assessed locally
- •Pathologic confirmation of strongly estrogen receptor positive (ER+) (defined as estrogen receptor [ER] ≥ 67% or Allred Score 6-8) by local institution protocol
- •Eastern Cooperative Oncology Group ECOG Performance Status (ECOG PS) of 0 to 2
- •Nottingham (Elston-Ellis) Grade 1 or 2
- •HER2- breast cancer (histologically confirmed) using American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines
- •Clinical T2 or T3 invasive breast cancer (per American Joint Committee on Cancer [AJCC] 8th edition clinical staging)
- •Clinical N0 or N1 invasive breast cancer (per American Joint Committee on Cancer [AJCC] 8th edition clinical staging)
- •MRI ≤ 35 days of registration
- •Must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects
- •Willing to provide blood and breast tissue samples for research purposes at specified timepoints for the duration of their participation in the trial.
排除标准
- •Bilateral invasive breast cancer; Inflammatory breast cancer defined as clinically significant erythema of the breast and/or documented dermal lymphatic invasion or bilateral invasive breast cancer (patients with pre-malignant disease or DCIS/LCIS in contralateral breast are eligible)
- •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 with the exception of:
- •Adequately treated in situ carcinoma of the cervix uteri
- •Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin
- •Any other malignancy with a life expectancy of less than 2 years
- •Any 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
- •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
- •Any of the following co-morbid conditions:
- •Known cataracts or retinopathy
- •History of deep vein thrombosis (DVT)/pulmonary embolism (PE)
- •Known activated protein C (APC) resistance, an inherited coagulation disorder
- •End stage kidney disease requiring dialysis
- •Evidence of the following laboratory abnormalities ≤ 28 days prior to registration:
- •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, or prior use of androgen-based therapy during the study or within 1 week of registration. If subject has a prior medical history of Depo-Provera®, it is recommended that the last dose of 3-month contraceptive agents are > 2.5 months from registration.
- •Allergy to endoxifen, goserelin, or exemestane or any of their components
- •Participation in another investigational clinical trial ≤ 6 months of registration
- •Known metastatic disease
研究组 & 干预措施
Treatment Cohort - Single Treatment Arm
(Z)-endoxifen 40mg capsules orally once daily for 4 weeks + goserelin 3.6 mg by subcutaneous implant approximately every 28 days. (Z)-endoxifen 40mg dose based on results of 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. And then go on to surgery within 3 weeks of Cycle 6 day 26.
If Ki-67 > 10% at Week 4, participant will complete early termination assessments.
干预措施: (Z)-endoxifen (Drug)
Treatment Cohort - Single Treatment Arm
(Z)-endoxifen 40mg capsules orally once daily for 4 weeks + goserelin 3.6 mg by subcutaneous implant approximately every 28 days. (Z)-endoxifen 40mg dose based on results of 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. And then go on to surgery within 3 weeks of Cycle 6 day 26.
If Ki-67 > 10% at Week 4, participant will complete early termination assessments.
干预措施: goserelin (Drug)
PK Cohort 80 mg + OFS
(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.
干预措施: goserelin (Drug)
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 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.
干预措施: (Z)-endoxifen (Drug)
PK Cohort 80 mg
(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.
干预措施: (Z)-endoxifen (Drug)
PK Cohort 80 mg + OFS
(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.
干预措施: (Z)-endoxifen (Drug)
结局指标
主要结局
PK Cohort - (Z)-endoxifen steady-state plasma concentrations
时间窗: After 4 weeks of treatment
(Z)-endoxifen steady-state plasma concentrations (Css) of evaluable subjects who completed at least one cycle of treatment (28 +/- 3 days)
PK Cohort - (Z)-endoxifen steady-state plasma concentrations
时间窗: After 4 weeks of treatment
(Z)-endoxifen steady-state plasma concentrations (Css) of evaluable subjects who completed at least one cycle of treatment (28 +/- 3 days)
For Analysis of Cohort A (Treatment Cohort): determine whether the week 4 Ki-67≤10% rate is at least 65%
时间窗: After 4 weeks of treatment
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.
For analysis Cohort B (Treatment Cohort): determine the objective tumor response rate at 24 weeks
时间窗: After 24 weeks of treatment
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.
次要结局
- Treatment Cohorts - Change in menopause quality of life (MENQOL)(baseline, up to 4 weeks, and up to 24 weeks)
- Treatment Cohorts - Nodal response rate(At time of surgery or up to 27 weeks)
- PK Cohort - Area under the plasma (Z)-endoxifen concentration-time curve from time zero to last measurable concentration(Days 1 and 28)
- PK Cohort - Area under the plasma (E)-endoxifen concentration-time curve from time zero to last measurable concentration(Days 1 and 28)
- PK Cohort - Accumulation and accumulation half-life(Days 1 and 28)
- PK Cohort - (Z)-endoxifen steady-state clearance(up to 28 days)
- PK Cohort - (E)-endoxifen steady-state clearance(up to 28 days)
- PK Cohort - Maximum plasma (Z)-endoxifen concentration(up to 28 days)
- PK Cohort - Maximum plasma (E)-endoxifen concentration(up to 28 days)
- PK Cohort - Time to plasma (Z)-endoxifen maximum concentration(up to 28 days)
- PK Cohort - Time to plasma (E)-endoxifen maximum concentration(up to 28 days)
- PK Cohort - plasma (Z)-endoxifen concentration(Day 1 up to 12 weeks and up to end of treatment or up to 24 weeks.)
- PK Cohort - plasma (E)-endoxifen concentration(Day 1 up to 12 weeks and up to end of treatment or up to 24 weeks.)
- PK Cohort - Area under the plasma (Z)-endoxifen concentration-time curve from time zero to last measurable concentration(Days 1 and 28)
- PK Cohort - Area under the plasma (E)-endoxifen concentration-time curve from time zero to last measurable concentration(Days 1 and 28)
- PK Cohort - Accumulation and accumulation half-life(Days 1 and 28)
- PK Cohort - (Z)-endoxifen steady-state clearance(up to 28 days)
- PK Cohort - (E)-endoxifen steady-state clearance(up to 28 days)
- PK Cohort - Maximum plasma (Z)-endoxifen concentration(up to 28 days)
- PK Cohort - Maximum plasma (E)-endoxifen concentration(up to 28 days)
- PK Cohort - Time to plasma (Z)-endoxifen maximum concentration(up to 28 days)
- PK Cohort - Time to plasma (E)-endoxifen maximum concentration(up to 28 days)
- PK Cohort - plasma (Z)-endoxifen concentration(Day 1 up to 12 weeks and up to end of treatment or up to 24 weeks.)
- PK Cohort - plasma (E)-endoxifen concentration(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(After 4 weeks of treatment)
- All Cohorts - Incidence and severity of adverse events per CTCAE by treatment(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(Informed consent up to follow up visit or up to 30 weeks)
- All Cohorts - Incidence of Dose Reductions(Informed consent up to end of treatment or up to 24 weeks)
- All Cohorts - Change in estradiol and estrone(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.(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(Day 1, up to 4 weeks, up to 12 weeks and up to 24 weeks)
- Treatment Cohorts - Radiographic Response Rate in the breast(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(At time of surgery or up to 27 weeks)
- Treatment Cohorts - Pre-Operative Endocrine Prognostic Index at time of surgery(At time of surgery or up to 27 weeks)
- Treatment Cohorts - Residual Cancer Burden at time of surgery(At time of surgery or up to 27 weeks)
- Treatment Cohorts - Conversion Rate(From baseline to time of surgery or up to 27 weeks)
- Treatment Cohorts - Actual Conversion Rate(At time of surgery or up to 27 weeks)
- Treatment Cohorts - Change in menopause quality of life (MENQOL)(baseline, up to 4 weeks, and up to 24 weeks)
- Treatment Cohorts - Nodal response rate(At time of surgery or up to 27 weeks)