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

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

Status
Active, not recruiting
Phases
Phase 2
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT02311933
Enrollment
81
Registered
2014-12-09
Start date
2015-05-28
Completion date
2027-02-02
Last updated
2026-08-28

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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

Brief summary

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

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.

Interventions

OTHERLaboratory Biomarker Analysis

Correlative studies

OTHERPharmacological Study

Correlative studies

DRUGTamoxifen Citrate

Given PO

Sponsors

National Cancer Institute (NCI)
Lead SponsorNIH

Study design

Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No

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

Design outcomes

Primary

MeasureTime frameDescription
Progression Free Survival (PFS)Assessed up to 5 yearsThe 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.

Secondary

MeasureTime frameDescription
Incidence of Adverse Events, Per Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0Up to 5 yearsFor 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.
Tumor Response Rate by Study Arm, Defined as the Number of Patients With a Complete or Partial ResponseUp to 5 yearsDefined 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.
Overall Survival Distribution by Study ArmThe time from registration to death due to any cause, assessed up to 5 yearsThe distribution of survival times will be estimated using the method of Kaplan-Meier.

Countries

United States

Contacts

PRINCIPAL_INVESTIGATORMatthew P Goetz

Alliance for Clinical Trials in Oncology

Participant flow

Participants by arm

ArmCount
Arm I (Z-endoxifen Hydrochloride)
Patients receive 80 mg z-endoxifen hydrochloride PO on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
41
Arm II (Tamoxifen Citrate)
Patients receive 20 mg 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.
40
Total81

Baseline characteristics

CharacteristicArm I (Z-endoxifen Hydrochloride)TotalArm II (Tamoxifen Citrate)
Age, Continuous64 years65 years66 years
Ethnicity (NIH/OMB)
Hispanic or Latino
1 Participants4 Participants3 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
39 Participants75 Participants36 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
1 Participants2 Participants1 Participants
Race (NIH/OMB)
American Indian or Alaska Native
1 Participants2 Participants1 Participants
Race (NIH/OMB)
Asian
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Black or African American
3 Participants5 Participants2 Participants
Race (NIH/OMB)
More than one race
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Unknown or Not Reported
1 Participants2 Participants1 Participants
Race (NIH/OMB)
White
36 Participants72 Participants36 Participants
Region of Enrollment
United States
41 participants81 participants40 participants
Sex: Female, Male
Female
41 Participants81 Participants40 Participants
Sex: Female, Male
Male
0 Participants0 Participants0 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
deaths
Total, all-cause mortality
1 / 410 / 39
other
Total, other adverse events
34 / 4136 / 39
serious
Total, serious adverse events
8 / 4111 / 39

Outcome results

Primary

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.

Time frame: Assessed up to 5 years

Population: All patients registered who began protocol treatment and were eligible for assessment were included in this analysis. One patient in Arm I was ineligible, two patients in Arm II were ineligible and one patient in Arm II did not receive treatment.

ArmMeasureValue (MEDIAN)
Arm I (Z-endoxifen Hydrochloride)Progression Free Survival (PFS)130 days
Arm II (Tamoxifen Citrate)Progression Free Survival (PFS)42 days
Secondary

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.

Time frame: Up to 5 years

Secondary

Overall Survival Distribution by Study Arm

The distribution of survival times will be estimated using the method of Kaplan-Meier.

Time frame: The time from registration to death due to any cause, assessed up to 5 years

Secondary

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.

Time frame: Up to 5 years

Other Pre-specified

Change in Biochemical Markers of Bone Turnover

For each of the markers of bone formation, the percent change after 2 courses of treatment from pre-treatment levels will be determined. A two-sided alpha = 0.01 z-test will be used to assess whether the percent change in a given bone absorption biomarkers differs with respect to treatment.

Time frame: Baseline to week 8 (after course 2)

Other Pre-specified

Deoxyribonucleic Acid (DNA) Alterations as Measured by Foundation Medicine

Data will be returned as presence or absence of various DNA alterations, along with description of type and location of the alteration. The nature of alterations in each pathway and gene will be described in tabular format. Association of presence or absence of DNA alterations with PFS will be assessed overall, by pathway, and by gene via Cox regression with the goal of evaluating hazard ratio estimates and confidence intervals. Alterations will be considered together as well as by type. Model fit and stability evaluated, and exact methods used if needed. Performed for both arms and within arms.

Time frame: Baseline

Other Pre-specified

Nuclear Receptor Coactivator 3 (SRC3) Immunohistochemistry Expression Levels

Within each treatment arm, a point and interval estimate of the difference in tumor response rate between those with metastatic SRC3-positive disease and those with metastatic SRC3-negative disease will be constructed using the properties of the binomial distribution. Also, a point and interval estimate of the odds of disease progression among those with metastatic SRC3-positive disease relative to those with metastatic SRC3-negative disease will be ascertained from the parameter estimates of fitting a proportional hazard model to the progression data.

Time frame: Baseline

Other Pre-specified

Pharmacodynamic Data

PK/PD relationships will be explored for effects of endoxifen on efficacy-related, adverse events or laboratory parameters of clinical interest. Exploratory/graphical analyses will be conducted for PK/PD evaluations and may be followed by model-based analyses. The data may be pooled with data from other/future studies for additional population PK/PD analyses.

Time frame: Baseline, 2-4, and 4-6 hours post-administration day 1 of course 1; baseline day 2 of course 1; pre-administration day 1 of course 3; pre-administration day 1 of course 9

Other Pre-specified

Pharmacogenetic Data

Examined in an exploratory and hypothesis-generating fashion.

Time frame: Baseline

Other Pre-specified

Pharmacokinetic (PK) Data

Examined in an exploratory and hypothesis-generating fashion. Pharmacokinetic-pharmacodynamic (PD) relationships will be explored for effects of endoxifen on efficacy-related, adverse events or laboratory parameters of clinical interest. Exploratory/graphical analyses will be conducted for PK/PD evaluations and may be followed by model-based analyses. The data may be pooled with data from other/future studies for additional population PK/PD analyses.

Time frame: Baseline, 2-4, and 4-6 hours post-administration day 1 of course 1; baseline day 2 of course 1; pre-administration day 1 of course 3; pre-administration day 1 of course 9

Other Pre-specified

Z-endoxifen Hydrochloride Area Under Curve (AUC)

A population PK will be developed using the software program NONMEM, Version 7. The model will be parameterized in terms of AUC (the primary endpoint), as well as clearance and volume of distribution. Criteria for model selection will include the likelihood ratio test, shrinkage estimates, reasonableness of parameter estimates, as well as goodness-of-fit plots. Attempts will be made to identify the covariates that affect drug behavior or those that explain variability in this patient population.

Time frame: Baseline, 2-4, and 4-6 hours post-administration day 1 of course 1; baseline day 2 of course 1; pre-administration day 1 of course 3; pre-administration day 1 of course 9

Source: ClinicalTrials.gov · Data processed: Aug 29, 2026