Tamoxifen Citrate or Z-Endoxifen Hydrochloride in Treating Patients With Locally Advanced or Metastatic, Estrogen Receptor-Positive, HER2-Negative Breast Cancer

Study Overview
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Brief Summary
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This randomized phase II trial studies how well tamoxifen citrate works compared with z-endoxifen hydrochloride in treating patients with breast cancer that has spread to nearby tissue or lymph nodes or other parts of the body and has estrogen receptors but not human epidermal growth factor receptor 2 (HER2) receptors on the surface of its cells. Estrogen can cause the growth of tumor cells. Hormone therapy using tamoxifen citrate or z-endoxifen hydrochloride may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known whether tamoxifen citrate or z-endoxifen hydrochloride is more effective in treating patients with breast cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess whether progression-free survival with z-endoxifen hydrochloride (HCl) relative to that with tamoxifen (tamoxifen citrate) is prolonged in postmenopausal women with local advanced or metastatic estrogen receptor (ER) positive/Her2 negative breast cancer. SECONDARY OBJECTIVES: I. To assess the safety profile of each of these agents in this patient population. II. To assess whether the tumor response rate (as determined using the Response Evaluation Criteria in Solid Tumors [RECIST] criteria) among those randomized to z-endoxifen HCl differs from that among those randomized to tamoxifen. III. To estimate the median progression-free survival time for those who receive z-endoxifen HCl after disease progression with tamoxifen. CORRELATIVE SCIENCE OBJECTIVES: I. To examine whether ER alpha alterations (defined as either ER activating mutations or ER amplification) are associated with longer progression-free survival (PFS) or higher response rates in the z-endoxifen HCl arm compared to the tamoxifen arm. II. To determine changes in lipid profiles comparing tamoxifen and z-endoxifen HCl. III. For each treatment, to evaluate changes in markers of bone formation and absorption after 12 weeks (4 cycles) of treatment. IV. For all patients and by treatment arm, to determine whether progression-free survival differs with respect to the sensitive to endocrine therapy (SET) index. V. To examine whether deoxyribonucleic acid (DNA) alterations as measured by Foundation medicine in all coding exons of 287 cancer-related genes as well as 78 polymorphisms in 34 absorption, distribution, metabolism, and excretion (ADME)-related genes are associated with longer PFS or higher response rates in the z-endoxifen HCl arm compared to the tamoxifen arm. VI. To assess whether the molecular characteristics identified in the tumor biopsies are detectable in the circulating tumor cells (CTCs) and/or cell-free DNA (cfDNA). VII. For each treatment arm: to examine changes in ER expression on CTCs, changes in estrogen receptor (ESR) mutations or amplification in CTCs or CfDNA and explore the impact of these changes on PFS and response rates. PHARMACOKINETICS AND PHARMACOGENOMICS OBJECTIVES: I. To further characterize pharmacokinetics, pharmacogenetics and metabolism of z-endoxifen HCl and tamoxifen. II. To determine the impact of the concentrations of tamoxifen and its metabolites on PFS in the tamoxifen arm. III. To determine the impact of the concentrations of z-endoxifen HCl and its metabolites on PFS in the endoxifen arm. V. To determine the impact of genetic variation in the enzymes responsible for tamoxifen and z-endoxifen HCl metabolism. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive z-endoxifen hydrochloride orally (PO) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive tamoxifen citrate PO once daily (QD) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression and bone metastases may cross over to Arm I and receive z-endoxifen hydrochloride starting no later than 28 days after documentation of disease progression. After completion of study treatment, patients are followed up yearly for up to 5 years.

Official Title
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A Randomized Phase II Trial of Tamoxifen Versus Z-Endoxifen HCL in Postmenopausal Women With Metastatic Estrogen Receptor Positive, HER2 Negative Breast Cancer

Conditions
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Recurrent Breast Carcinoma, Stage III Breast Cancer AJCC v7, Stage IIIA Breast Cancer AJCC v7, Stage IIIB Breast Cancer AJCC v7, Stage IIIC Breast Cancer AJCC v7, Stage IV Breast Cancer AJCC v6 and v7

Intervention / Treatment
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* Drug: Endoxifen Hydrochloride
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Drug: Tamoxifen Citrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PRE-REGISTRATION ELIGIBILITY CRITERIA Women who agree to undergo a standard of care core biopsy of recurrent or metastatic breast cancer to confirm the ER+ (>= 10% nuclear staining) and HER2 negative status Patient must have been previously treated with an aromatase inhibitor (either letrozole, anastrozole or exemestane) either in the adjuvant or metastatic setting, and have one of the following types of primary or secondary endocrine resistant disease Primary clinical resistance is defined as one of the following: Recurrence within the first 2 years of adjuvant endocrine therapy while on aromatase inhibitor therapy Progression within first 6 months of initiating first-line endocrine therapy (either aromatase inhibitor or fulvestrant containing regimen) for the treatment of metastatic breast cancer Secondary clinical resistance is defined as one of the following: Recurrence after year 2 while receiving adjuvant aromatase inhibitor therapy, or within 12 months of completing adjuvant aromatase inhibitor therapy Progression occurring 6 or more months after initiating the first endocrine therapy for metastatic disease (either fulvestrant or aromatase inhibitor containing regimen) Patients with a history of measurable disease as defined by RECIST criteria or bone only disease are eligible; Note: those patients with non-measurable disease and bone metastases are eligible No history of tumors involving spinal cord or heart No current evidence of visceral crisis or lymphangitic spread No known brain metastases Women must be postmenopausal Postmenopausal status is verified by: Prior bilateral surgical oophorectomy, or Age >= 60 years, or Age < 60 with no menses for > 1 year with follicle-stimulating hormone (FSH) and estradiol levels within post menopausal range, according to institutional standard Prior treatment No more than two prior chemotherapy regimens in the metastatic setting Prior treatment with an aromatase inhibitor (either anastrozole, letrozole or exemestane), either in the adjuvant or metastatic setting is required Unlimited prior endocrine regimens in the metastatic setting, which may have included an everolimus or cyclin dependent kinase (CDK) 4/6 inhibitor (such as palbociclib, abemaciclib or ribociclib) containing regimen Prior tamoxifen treatment is allowed in the adjuvant setting, but patients must not have experienced relapse within 1 year of stopping tamoxifen No prior treatment with tamoxifen in the metastatic setting No prior treatment with endoxifen Patients who have not fully recovered from acute, reversible effects of prior therapy regardless of interval since last treatment are not eligible to participate in this study EXCEPTION: neuropathies-if grade 2 neuropathies have been stable for at least 3 months since completion of prior treatment patient is eligible Not receiving any medications or substances that are strong inhibitors of cytochrome P450 family 2, subfamily D, polypeptide 6 (CYP2D6) Not receiving any other investigational agents No uncontrolled intercurrent illness including, but not limited to: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Uncontrolled symptomatic cardiac arrhythmia Uncontrolled hypertension (defined as blood pressure > 160/90) None of the following co-morbid conditions: Cataracts of grade 2 or greater as per Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 Retinopathy of grade 2 or greater as per CTCAE version 4.0 Note: patients that have cataracts that do not require surgery are eligible Note: serious adverse events will be reported on CTEP-Adverse Event Reporting System (AERS) using CTCAE version (v)5.0 Deep vein thrombosis/pulmonary embolism (DVT/PE) within the past 6 months Note: patients that are on anticoagulant therapy for maintenance are eligible as long as the DVT and/or PE occurred > 6 months prior to enrollment, and there is no evidence for active thrombosis (either DVT or PE) No other active second malignancy other than non-melanoma skin cancers within 3 years of pre-registration; a second malignancy is not considered active if all treatment for that malignancy is completed and the patient has been disease-free for at least 3 years prior to pre-registration Eastern Cooperative Oncology Group (ECOG) performance status: 0-2 Able to swallow oral formulation of the study agent Hemoglobin >= 9 g/dL Platelet count >= 75,000/mm^3 Creatinine =< 1.5 x upper limits of normal (ULN) Total bilirubin =< 1.5 x upper limits of normal (ULN) Aspartate aminotransferase (AST) =< 2.5 x upper limits of normal (ULN); for patients with liver metastasis: =< 5 x upper limits of normal (ULN) REGISTRATION ELIGIBILITY CRITERIA Patients with either measurable disease as defined by RECIST criteria or bone only disease are eligible; Note: those patients with both non-measurable disease and bone metastases are eligible Non-measurable bone only disease: Non-measurable bone only disease may include any of the following: blastic bone lesions, lytic bone lesions without a measurable soft-tissue component, or mixed lytic-blastic bone lesions without a measurable soft-tissue component Lytic bone lesions, with an identifiable soft tissue component, evaluated by computed tomography (CT) or magnetic resonance imaging (MRI), can be considered as measurable lesions if the soft tissue component otherwise meets the definition of measurability previously described No tumors involving spinal cord or heart No visceral crisis, lymphangitic spread or known brain metastases: visceral crisis is not the mere presence of visceral metastases, but implies severe organ dysfunction as assessed by symptoms and signs, laboratory studies, and rapid progression of disease Histologic confirmation, from the A011203 pre-registration biopsy, by institutional/local pathologist of either locally advanced or metastatic breast cancer that is estrogen receptor positive and HER2 negative; those patients with bone only disease with either no tumor or insufficient tumor for ER/progesterone receptor (PR) and HER2 staining after the bone biopsy are still eligible to participate in this study Estrogen receptor positive disease is defined as > 10% nuclear staining HER2 negative disease as per 2013 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines, one of the following must apply: 0 or 1+ by immunohistochemistry (IHC) and not amplified by in situ hybridization (ISH) 0 or 1+ by IHC and ISH not done 2+ by IHC and not amplified by ISH or IHC not done and not amplified by ISH None of the following therapies are allowed prior to registration: Chemotherapy =< 2 weeks Immunotherapy =< 2 weeks Biologic therapy =< 2 weeks Hormonal therapy =< 2 weeks Monoclonal antibodies =< 2 weeks Radiation therapy =< 2 weeks Anti-Her-2 or other targeted (e.g. mammalian target of rapamycin [mTOR]) therapy =< 2 weeks NOTE : Any toxicities derived from these therapies must be =< grade 2 prior to starting study therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (z-endoxifen hydrochloride)<br>Patients receive z-endoxifen hydrochloride PO on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Endoxifen Hydrochloride<br>* Given PO<br>* Other names: Z-Endoxifen Hydrochloride;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>|
| Experimental: Arm II (tamoxifen citrate)<br>Patients receive tamoxifen citrate PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression and bone metastases may cross over to Arm I and receive z-endoxifen hydrochloride starting no later than 28 days after documentation of disease progression. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Drug: Tamoxifen Citrate<br>* Given PO<br>* Other names: Zemide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | The primary endpoint is progression-free survival (PFS) defined as the time from randomization to documentation of local, regional or distant disease progression or death without progression of disease. | Assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events, Per Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | For a given adverse event (AE), the proportion of patients on each treatment arm who report developing a grade 2-5 of this AE will be determined. | Up to 5 years | 
| Tumor Response Rate by Study Arm, Defined as the Number of Patients With a Complete or Partial Response | Defined by Response Evaluation Criteria in Solid Tumors on 2 consecutive evaluations at least 6 weeks apart, divided by the total number of eligible patients who began study treatment. A 90% binomial confidence interval will be constructed for the true response rate. | Up to 5 years | 
| Overall Survival Distribution by Study Arm | The distribution of survival times will be estimated using the method of Kaplan-Meier. | The time from registration to death due to any cause, assessed up to 5 years |