Tamoxifen Citrate or Z-Endoxifen Hydrochloride in Treating Patients With Locally Advanced or Metastatic, Estrogen Receptor-Positive, HER2-Negative Breast Cancer
Phase 2 – studying effectiveness and dosage
Conditions:
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
Sponsor: National Cancer Institute (NCI)
trial.available_in:
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Overview
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.
Description
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)
Who can participate
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
Interventions
Endoxifen Hydrochloride
DRUG
Laboratory Biomarker Analysis
OTHER
Pharmacological Study
OTHER
Tamoxifen Citrate
DRUG
Locations
561
United States (561)
Pali Momi Medical Center
‘Aiea , Hawaii
Queen's Cancer Center - Pearlridge
‘Aiea , Hawaii
The Cancer Center of Hawaii-Pali Momi
‘Aiea , Hawaii
Providence Regional Cancer System-Aberdeen
Aberdeen , Washington
Jefferson Abington Hospital
Abington , Pennsylvania
Cleveland Clinic Akron General
Akron , Ohio
University of New Mexico Cancer Center
Albuquerque , New Mexico
Lehigh Valley Hospital-Cedar Crest
Allentown , Pennsylvania
Mary Greeley Medical Center
Ames , Iowa
McFarland Clinic - Ames
Ames , Iowa
Community Hospital of Anaconda
Anaconda , Montana
Cancer Care Center at Island Hospital
Anacortes , Washington
Kaiser Permanente-Anaheim
Anaheim , California
Anchorage Associates in Radiation Medicine
Anchorage , Alaska
Anchorage Radiation Therapy Center
Anchorage , Alaska
Alaska Breast Care and Surgery LLC
Anchorage , Alaska
Alaska Oncology and Hematology LLC
Anchorage , Alaska
Alaska Regional Hospital
Anchorage , Alaska
Alaska Women's Cancer Care
Anchorage , Alaska
Anchorage Oncology Centre
Anchorage , Alaska
Katmai Oncology Group
Anchorage , Alaska
Providence Alaska Medical Center
Anchorage , Alaska
Trinity Health Saint Joseph Mercy Hospital Ann Arbor
Ann Arbor , Michigan
PCR Oncology
Arroyo Grande , California
AdventHealth Infusion Center Asheville
Asheville , North Carolina
University Cancer and Blood Center LLC
Athens , Georgia
Northside Hospital
Atlanta , Georgia
MultiCare Auburn Medical Center
Auburn , Washington
Sutter Auburn Faith Hospital
Auburn , California
Sutter Cancer Centers Radiation Oncology Services-Auburn
Auburn , California
Augusta University Medical Center
Augusta , Georgia
Harold Alfond Center for Cancer Care
Augusta , Maine
Rush-Copley Medical Center
Aurora , Illinois
Virginia Mason Bainbridge Island Medical Center
Bainbridge Island , Washington
Saint Alphonsus Cancer Care Center-Baker City
Baker City , Oregon
AIS Cancer Center at San Joaquin Community Hospital
Bakersfield , California
Kaiser Permanente-Baldwin Park
Baldwin Park , California
Mercy Oncology and Hematology - Clayton-Clarkson
Ballwin , Missouri
Eastern Maine Medical Center
Bangor , Maine
Flaget Memorial Hospital
Bardstown , Kentucky
Ochsner Health Center-Summa
Baton Rouge , Louisiana
Bronson Battle Creek
Battle Creek , Michigan
Overlake Medical Center
Bellevue , Washington
Swedish Cancer Institute-Eastside Oncology Hematology
Bellevue , Washington
Kaiser Permanente-Bellflower
Bellflower , California
PeaceHealth Saint Joseph Medical Center
Bellingham , Washington
Gaston Hematology and Oncology Associates-Belmont
Belmont , North Carolina
Strecker Cancer Center-Belpre
Belpre , Ohio
Sanford Joe Lueken Cancer Center
Bemidji , Minnesota
Saint Charles Health System
Bend , Oregon
Alta Bates Summit Medical Center-Herrick Campus
Berkeley , California
Lehigh Valley Hospital - Muhlenberg
Bethlehem , Pennsylvania
Billings Clinic Cancer Center
Billings , Montana
Saint Vincent Healthcare
Billings , Montana
Sanford Bismarck Medical Center
Bismarck , North Dakota
OSF Saint Joseph Medical Center
Bloomington , Illinois
Illinois CancerCare-Bloomington
Bloomington , Illinois
Saint Alphonsus Cancer Care Center-Boise
Boise , Idaho
Saint Luke's Cancer Institute - Boise
Boise , Idaho
Central Care Cancer Center - Bolivar
Bolivar , Missouri
Parkland Health Center-Bonne Terre
Bonne Terre , Missouri
McFarland Clinic - Boone
Boone , Iowa
Bozeman Health Deaconess Hospital
Bozeman , Montana
Essentia Health Saint Joseph's Medical Center
Brainerd , Minnesota
Cox Cancer Center Branson
Branson , Missouri
Lafayette Family Cancer Center-EMMC
Brewer , Maine
Trinity Health IHA Medical Group Hematology Oncology - Brighton
Brighton , Michigan
Trinity Health Medical Center - Brighton
Brighton , Michigan
State University of New York Downstate Medical Center
Brooklyn , New York
Saint Joseph Regional Cancer Center
Bryan , Texas
Providence Saint Joseph Medical Center/Disney Family Cancer Center
Burbank , California
Highline Medical Center-Main Campus
Burien , Washington
Mills-Peninsula Medical Center
Burlingame , California
Saint James Community Hospital and Cancer Treatment Center
Butte , Montana
Saint Alphonsus Cancer Care Center-Caldwell
Caldwell , Idaho
Sutter Cancer Centers Radiation Oncology Services-Cameron Park
Cameron Park , California
Trinity Health Medical Center - Canton
Canton , Michigan
Illinois CancerCare-Canton
Canton , Illinois
Cleveland Clinic Mercy Hospital
Canton , Ohio
Aultman Health Foundation
Canton , Ohio
Trinity Health IHA Medical Group Hematology Oncology - Canton
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