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Phase I Study of Z-Endoxifen as a Hormonal Therapy for Breast Cancer

Phase 1
18 Years
Open (Enrolling)
Estrogen Receptor-positive Breast Cancer, Hot Flashes, Recurrent Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer

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Trial Information

Phase I Study of Z-Endoxifen as a Hormonal Therapy for Breast Cancer


l. To determine the maximum-tolerated dose of Z-endoxifen hydrochloride in women with
metastatic estrogen-receptor positive (ER+) breast cancer.

II. To describe the safety profile of Z-endoxifen hydrochloride at each of the doses

III. To evaluate changes in vision after 2 courses of treatment. IV. To gather preliminary
data on the clinical benefit in terms of tumor response rate and progression-free survival.

V. To explore changes in the uterine lining thickness after 2 courses of treatment
(approximately 56 days) in post-menopausal women (Expansion cohort).

VI. To evaluate the changes in the frequency and severity of hot flashes after 2 courses of
treatment (Expansion cohort).

VII. Evaluate changes in irritability scale using a validated Irritability questionnaire
(Expansion cohort).

VIII. To evaluate changes in markers of bone formation and absorption after 2 cycles of
treatment (Expansion cohort).

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


I. To characterize the plasma pharmacokinetics and urinary excretion of Z-endoxifen
hydrochloride 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, PR, SRC1, SRC3, as well as the
IGF1R/PI3K/AKT/mTOR pathway as outlined in section 17 and Ki67 after 1 cycle of treatment
(approximately 28 days).

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

Patients receive Z-endoxifen hydrochloride orally on days 1-28. Courses repeat every 28 days
in the absence of disease progression or unacceptable toxicity. Blood and urine samples are
collected at baseline and periodically during study for pharmacokinetics, pharmacogenetics,
and biomarker studies. Patients in the expansion cohort also undergo tumor tissue sample
collection for correlative studies. Patients may complete a diary on the frequency and
severity of hot flashes at baseline and on day 28 of course 1. They may also complete an
irritability questionnaire at baseline and periodically during study.

After completion of study therapy, patients are followed up for 30 days.

Inclusion Criteria:

- Histologically confirmed diagnosis of metastatic or locally recurrent breast cancer

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

- Lesion type:

- For the dose-escalation cohort: evaluable or measurable disease

- For the expansion cohort(s): at least one measurable non-nodal lesion or lymph
node as defined by RECIST 1.1.

- A non-nodal lesion is considered measurable if its longest diameter can be
accurately measured as ≥2.0 cm with chest xray, or as ≥1.0 cm with CT scan,
CT component of a PET/CT, or MRI

- A superficial non-nodal lesion is measurable if its longest diameter is ≥
1.0 cm in diameter as assessed using calipers (e.g., skin nodules) or

- In the case of skin lesions, documentation by color photography,
including a ruler to estimate the size of the lesion, is recommended

- A lymph node is considered a measurable target lymph node if its short axis
is ≥ 1.5 cm when assessed by CT scan (CT scan slice thickness must be no
greater than 5 mm)

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

- No tumors involving the spinal cord or heart

- No uncontrolled brain metastases

- Brain metastases that have been treated by surgery or radiotherapy, and the
patient has been neurologically stable and off steroids for ≥ 12 weeks, allowed

- Pre- or post-menopausal female (dose-escalation cohort) OR post-menopausal with an
intact uterus (no prior hysterectomy) (expansion cohort)

- ECOG performance status 0-1

- Life expectancy >16 weeks

- ANC ≥ 1,000/μL

- Platelet count ≥ 75,000/μL

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST and ALT ≤ 2.5 times ULN (< 5 times ULN for liver metastases)

- Creatinine ≤ 1.5 times ULN

- 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)

- Willingness to undergo pelvic ultrasounds (postmenopausal women only)

- 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

- Negative pregnancy test

- Not pregnant or nursing

- Women of childbearing potential must agree to use adequate contraception

- Capable of swallowing 20-mg capsules

- None of the following:

- Stroke ≤ 6 months prior to registration

- Seizures ≤ 3 months prior to registration

- Deep vein thrombosis (DVT) or pulmonary embolism (PE) ≤ 12 months prior to

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

- Crystalline retinopathy

- Abnormal uterine bleeding ≤ 1 year prior to registration

- No personal history of coagulopathy

- No 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)

- No clinically symptomatic cataracts requiring imminent surgery

- Patients who have cataracts that do not require surgery are eligible

- No other invasive malignancy that has been diagnosed or has recurred < 2 years prior
to registration except non-melanotic skin cancer or carcinoma-in-situ of the cervix

- No co-morbid systemic illnesses or other severe concurrent disease that, 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

- No 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

- No other concurrent ancillary therapy considered investigational

- Any number of prior systemic therapy regimens is allowed (dose-escalation cohort)

- Prior systemic 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) (dose-escalation cohort)

- One or two prior hormone-containing regimens in the metastatic setting (expansion

- A prior hormone-containing regimen in the adjuvant setting is not required

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

- Prior chemotherapy in the adjuvant setting is not required (expansion cohort)

- More than 3 weeks since prior and no other concurrent chemotherapy, immunotherapy,
biologic therapy, hormonal therapy, monoclonal antibodies, or radiotherapy and
recovered to ≤ grade 1 toxicity

- More than 3 weeks since prior and no concurrent anti-HER-2 directed therapy

- No prior Z-endoxifen hydrochloride

- No plans to begin bisphosphonates after registration or began a bisphosphonate
regimen < 90 days before registration

- Patients on a stable dose of bisphosphonates for > 90 days prior to registration
are eligible

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD defined as the highest dose level where at most 1 of 6 patients develops a dose limiting toxicity and 2 or more of the 3-6 patients treated at the next higher dose level develop a dose limiting toxicity using CTCAE version 4.0

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Matthew Goetz

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

March 2011

Completion Date:

Related Keywords:

  • Estrogen Receptor-positive Breast Cancer
  • Hot Flashes
  • Recurrent Breast Cancer
  • Stage IIIC Breast Cancer
  • Stage IV Breast Cancer
  • Breast Neoplasms
  • Hot Flashes



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