Z-Endoxifen Hydrochloride in Treating Patients With Metastatic or Locally Recurrent Estrogen Receptor-Positive Breast Cancer

PRIMARY OBJECTIVES:

l. To determine either the maximum-tolerated dose (MTD) of Z-endoxifen hydrochloride or the
dose level associated with endoxifen steady state concentration (Css) of at least 2 uM in
women with metastatic estrogen-receptor positive (ER+) breast cancer. (Dose Escalation
Cohort) II. To describe the safety profile of Z-endoxifen (Z-endoxifen hydrochloride) at each
of the doses examined. (Dose Escalation Cohort) III. To evaluate changes in vision after 2
cycles of treatment. (Dose Escalation Cohort) IV. To gather preliminary data on the clinical
benefit in terms of tumor response rate and progression-free survival. (Dose Escalation
Cohort) V. To evaluate the changes in the frequency and severity of hot flashes after 2
cycles of treatment. (Expansion Cohort) VI. Evaluate changes in irritability scale using a
validated irritability questionnaire. (Expansion Cohort) VII. To evaluate changes in markers
of bone formation and absorption after 2 cycles of treatment. (Expansion Cohort) XIII. To
evaluate changes in vision after 2 cycles of treatment. (Expansion Cohort).

IX. To further characterize the safety profile of Z-endoxifen. (Expansion Cohort)

SECONDARY OBJECTIVES:

I. To characterize the plasma pharmacokinetics and urinary excretion of Z-endoxifen at each
of the doses examined.

II. For patients beginning in dose level 7 as well as the expansion cohorts, we will describe
any changes in tumor expression of ER (both full length and truncated forms), progesterone
receptor (PR), steroid receptor co-activator (SRC)1, SRC3, as well as the insulin-like growth
factor receptor (IGF)1R/phosphatidylinositol 3 kinase (PI3K)/v-akt Murine Thymoma Viral
Oncogene Homolog 1 (AKT)/mammalian target of rapamycin (mTOR) pathway and
proliferation-related Ki-67 antigen (Ki67) after 1 cycle of treatment (approximately 28
days).

III. To determine the frequency of estrogen receptor 1 (ESR1) mutations and the presence of
antitumor activity (response rate and progression free survival [PFS]) in all patients whose
tumors harbor ESR1 alterations.

IV. To determine whether the ESR1 mutations identified in pre-treatment tumor biopsies can be
detected in matched plasma cell free deoxyribonucleic acid (DNA) from the same patients.

OUTLINE: This is a dose-escalation study followed by an expansion cohort study.

Patients receive Z-endoxifen hydrochloride orally (PO) on days 1-28. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then at 3
months.

Inclusion Criteria:

- Histologically confirmed diagnosis of metastatic or locally recurrent breast cancer

- ER positive defined as > 1% nuclear staining on the biopsy that was obtained at the
confirmation of metastatic or locally recurrent disease

- Lesion type of either evaluable or measurable disease

- Pre- or post-menopausal female

- For the expansion cohorts: tumor that is accessible for biopsy

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

- Life expectancy > 16 weeks

- Capable of understanding investigational nature, potential risks and benefits of the
study and able to provide written informed consent

- Absolute neutrophil count (ANC) >= 1,000/uL

- Platelet count >= 75,000/uL

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
institutional ULN (< 5 x institutional ULN if liver function test [LFT] elevations due
to liver metastases)

- Creatinine =< 1.5 x institutional ULN

- Women with human epidermal growth factor (HER)-2 positive disease must have received
and progressed on at least one prior anti-HER-2 directed regimen (trastuzumab,
lapatinib) for their metastatic disease

- For dose escalation cohort:

- Any number of prior systematic therapy regimens is allowed

- NOTE: prior systematic therapy in the adjuvant setting is not required

- At least one prior hormone containing regimen in the metastatic setting
(tamoxifen if pre-menopausal; aromatase inhibitor if post-menopausal)

- NOTE: exception: patients that fail (defined as the development of
metastatic disease while receiving an adjuvant hormone containing
regimen of tamoxifen for premenopausal and aromatase inhibitor for
postmenopausal) are eligible and not required to receive additional
hormonal containing regimens prior to enrollment

- At least one prior chemotherapy containing regimen in adjuvant and/or
metastatic setting

- For the expansion cohort(s):

- At least one prior hormone containing regimen in the metastatic setting
(tamoxifen if pre-menopausal; aromatase inhibitor if post-menopausal)

- NOTE: exception: patients that fail (defined as the development of
metastatic disease while receiving an adjuvant hormone containing
regimen of tamoxifen for premenopausal and aromatase inhibitor for
postmenopausal) are eligible and not required to receive additional
hormonal containing regimens prior to enrollment

- NOTE: a prior hormone containing regimen in the adjuvant setting is not
required; a hormonal regimen containing everolimus is allowed

- Either 1 or 2 prior chemotherapy regimens are allowed but not required such
that both are in the metastatic setting or one is in the adjuvant setting
and one in the metastatic setting (note, an anthracycline and taxane based
regimen delivered in the adjuvant setting would be considered one regimen)

- Willingness to return to Mayo Clinic Rochester, Arizona, or Florida during treatment
phase of the trial

- Dose Escalation cohort only:

- Mandatory Translational Research Components

- Willingness to provide biologic specimens (blood and urine)

- Dose Escalation cohorts beginning at 160 mg/day: Mandatory Translational Research
Components

- Willingness to provide biologic specimens (tissue)

- Dose Expansion cohort(s):

- Mandatory Translational Research Components

- Willingness to provide biologic specimens (blood, tissue and urine)

- Note: The goals of this study include assessment of the biologic effects on
surrogate markers of Z-endoxifen and therefore, are contingent upon
availability of the biologic specimens

- Women of childbearing potential only: negative serum pregnancy test done =< 48 hours
prior to registration

- Capable of swallowing 20-mg capsules

Exclusion Criteria:

- Any of the following therapies prior to registration:

- Chemotherapy =< 3 weeks

- Immunotherapy =< 3 weeks

- Biologic therapy =< 3 weeks

- Hormonal therapy =< 3 weeks

- Monoclonal antibodies =< 3 weeks

- Radiation therapy =< 3 weeks

- Anti-Her-2 directed therapy =< 3 weeks

- Prior endoxifen therapy

- Prior history of:

- Stroke =< 6 months prior to registration

- Seizures =< 3 months prior to registration

- Deep vein thrombosis (DVT) or pulmonary embolism (PE) =< 12 months prior to
registration

- Two or more episodes of DVT and/or PE =< 5 years prior to registration

- Crystalline retinopathy

- Abnormal uterine bleeding =< 1 year prior to registration

- Personal history of coagulopathy

- Active DVT and/or PE requiring anti-coagulant therapy

- Patients who are on anti-coagulant therapy for maintenance are eligible as long
as the DVT and/or PE was > 12 months prior to enrollment and there is no evidence
for active thrombosis (either DVT or PE)

- Clinically symptomatic cataracts requiring imminent surgery

- Note: patients that have cataracts that do not require surgery are eligible

- Other invasive malignancy that has been diagnosed or has recurred < 2 years prior to
registration; EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the cervix

- Any co-morbid systemic illnesses or other severe concurrent disease which, in the
judgment of the investigator, would make the patient inappropriate for entry into this
study or interfere significantly with the proper assessment of safety and toxicity of
the prescribed regimens

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, hypertension, or psychiatric illness/social situations that would limit
compliance with study requirements

- Failure to fully recover from acute, reversible effects of prior chemotherapy
regardless of interval since last treatment; EXCEPTION: neuropathies - if grade 2
neuropathies have been stable for at least 3 months since completion of prior
treatment patient is eligible

- Tumors involving the spinal cord or heart

- Uncontrolled brain metastases

- Note: brain metastases are not permitted on study unless the metastases have been
treated by surgery or radiotherapy, and the patient has been neurologically
stable and off steroids for >= 12 weeks

- Plans to begin bisphosphonates or denosumab after registration or began a
bisphosphonate or denosumab regimen < 90 days before registration

- Note: patients on a stable dose of bisphosphonates or denosumab for > 90 days
prior to registration are eligible

- Any of the following:

- Pregnant women

- Nursing women

- Women of childbearing potential who are unwilling to employ adequate
contraception

- Other concurrent chemotherapy or anti HER2 therapy, immunotherapy, radiotherapy, or
any ancillary therapy considered investigational (utilized for a non-Food and Drug
Administration [FDA]-approved indication and in the context of a research
investigation)