Endoxifen in Adults With Hormone Receptor Positive Solid Tumors

BACKGROUND:

- Genetic polymorphisms in CYP2D6 and concomitant medications alter tamoxifen metabolism,
limiting exposure to the active metabolite endoxifen. These factors are associated with
a higher rate of recurrence and shorter disease-free survival in breast cancer patients
receiving tamoxifen.

- Administration of endoxifen directly to patients is anticipated to bypass the effects of
CYP2D6 polymorphisms and concomitant medications and provide adequate active drug levels
in all treated patients, resulting in clinical benefit.

- 16 alpha-[(18)F]-fluoro-17 beta estradiol (FES) is an investigational radiolabeled
imaging agent used with positron emission tomography (PET) to investigate tumor estrogen
receptor activity

OBJECTIVES:

Primary:

- Establish the safety and tolerability of oral endoxifen (Z-Endoxifen HCl) administered
on a daily schedule to patients with refractory hormone receptor positive solid tumors
(breast or other tumors), desmoid tumors, or gynecologic tumors.

- Establish the maximum tolerated dose (MTD) of oral Z-endoxifen HCl administered on a
daily schedule.

Secondary:

-Determine the pharmacokinetics of oral Z-endoxifen (HCl form).

Exploratory:

-Evaluate the change in [(18)F]FES uptake using PET/CT in hormone receptor-positive tumors
before and after treatment with oral Z-endoxifen-HCI.

ELIGIBILITY:

- Adults with histologically documented hormone receptor positive solid tumors (breast or
other tumors), desmoid tumors, or gynecologic tumors.

- Patients with breast cancer must have had at least one prior chemotherapy regimen and
one prior hormonal regimen for metastatic disease. All other patients must have disease
that has progressed following at least one line of standard therapy.

- No major surgery, radiation, hormonal, or chemotherapy within 4 weeks prior to study
enrollment, and recovered from toxicities of prior therapies to at least eligibility
levels.

- Patients in the 6-patient expansion cohort at the MTD will be asked to undergo optional
tumor biopsies for research purposes.

STUDY DESIGN:

- Z-endoxifen will be administered orally once a day in 28-day cycles.

- Dose escalation will proceed until the MTD is established or targeted maximum dose (DL8)
reached. Six additional patients will then be entered in an expansion cohort to assess
pharmacodynamics and pharmacokinetics

- When imaging agent is available, optional FES PET/CT scans will be performed at baseline
and 1-3 hours after Z-endoxifen treatment once during week 1 of cycle 1.

- As a relative bioavailability study, 6 patients in the expansion cohort will be given a
single dose of the free base form of Z-endoxifen on day 1 and will then continue on
study taking Z-endoxifen HCl; blood and urine will be collected for PK at baseline, on
cycle 1 days 1 and 2, and on cycle 2 day 1. Please note: As of Febuary 2017, we will no
longer evaluate the free base form of Z-endoxifen in the expansion cohort due to drug
supply issues.

- INCLUSION CRITERIA:

Patients with the following types of histologically documented solid tumors:

- ER +/PR+, ER+/PR-, or ER-/PR+ breast cancer

- Gynecologic tumors (endometrial, ovarian, uterine, fallopian tube, peritoneal, etc.)

- Desmoid tumors

- Tumors that are ER+ or PR+ by immunohistochemistry (including low-level expression)
such as non-small cell lung, colorectal, and prostate

Patients with breast cancer must have had at least one prior chemotherapy regimen for
metastatic disease. Additionally, patients with breast cancer must have received prior
tamoxifen and/or aromatase inhibitor therapy (if postmenopausal) with at least one hormonal
regimen in the metastatic setting. Patients with HER2+ breast cancer must have progressed
after at least one prior HER2-directed regimen (trastuzumab, lapatinib) for metastatic
disease.

All other patients must have disease that has progressed following at least one line of
standard therapy. Prior therapy with tamoxifen is allowed.

Patients enrolled based on tumor ER/PR status must have ER/PR status confirmed by the
Laboratory of Pathology, NIH. ER/PR status will be determined on a metastatic site, if
possible; otherwise, the original site or available tissue will be acceptable.

Patients must have recovered to at least eligibility levels following any display of
adverse events and/or toxicity due to prior chemotherapy or biologic therapy. They must not
have had hormonal therapy, chemotherapy or biologic therapy within 4 weeks prior to
entering the study (6 weeks for nitrosoureas or mitomycin C, or UCN-01). Patients must be
greater than or equal 2 weeks since any prior administration of study drug in a Phase 0
study (also referred to as an "early Phase I study" or "pre-Phase I study" where a
sub-therapeutic dose of drug is administered) at the PI's discretion. Patients must be
greater than or equal to 4 weeks since any prior radiation or major surgery. However,
patients receiving bisphosphonates or therapeutic anticoagulation are eligible for this
trial.

Age greater than or equal 18 years

The Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2

Life expectancy > 3 months

Patients must have normal or adequate organ and marrow function as defined below:

Absolute neutrophil count greater than or equal to 1,500/microL

Platelets greater than or equal to 100,000/micorL

Total bilirubin within less than or equal to 1.5 times institutional upper limit of normal

AST (SGOT)/ALT (SGPT) less than or equal to 2.5 times institutional upper limit of normal

Creatinine < 1.5 times upper limit of normal

OR

Creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with
creatinine levels greater than or equal to 1.5 times upper limit of normal.

The effects of Z-endoxifen on the developing human fetus are unknown. For this reason,
women of childbearing potential and men must agree to use adequate nonhormonal
contraception (barrier method of birth control or abstinence) prior to study entry, for the
duration of study participation, and for 2 months after discontinuation from the study.
Women of childbearing potential must have a negative pregnancy test in order to be
eligible. Should a woman become pregnant or suspect she is pregnant while participating in
this study, she should inform her treating physician immediately. Because there is an
unknown but potential risk for adverse events in nursing infants secondary to treatment of
the mother with Z-endoxifen, breastfeeding should be discontinued if the mother is treated
with Z-endoxifen.

Ability to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

Patients receiving any other investigational agents.

Patients with known brain metastases are excluded from this clinical trial, with the
exception of patients whose brain metastatic disease status has remained stable for greater
than or equal to 3 months after treatment of the brain metastases, without steroids or
anti-seizure medications. These patients may be enrolled at the discretion of the principal
investigator.

Patients with clinically significant illnesses which could compromise participation in the
study, including, but not limited to, uncontrolled infection, uncontrolled diabetes,
uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris,
myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia,
stroke/cerebrovascular accident within the past 6 months, or psychiatric illness/social
situations that in the investigator s opinion would make it undesirable for the patient to
participate in the trial, or which would jeopardize compliance with the protocol.

Patients with untreated spinal cord metastases or metastases close to vital organs (as
determined by the principal investigator) are excluded because of the risk of hormonal
flare.

Patients with a history of deep vein thrombosis must be on anti-coagulation therapy prior
to enrollment. Patients requiring prophylactic anti-coagulation are eligible.