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

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.

TERTIARY 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.

VIII. To further characterize pharmacokinetics, pharmacogenetics and metabolism of
z-endoxifen HCl and tamoxifen.

IX. To determine the impact of the concentrations of tamoxifen and its metabolites on PFS in
the tamoxifen arm.

X. To determine the impact of the concentrations of z-endoxifen HCl and its metabolites on
PFS in the endoxifen arm.

XI. 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.

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