Know Cancer

or
forgot password

Phase I Trial of Z-Endoxifen in Adults With Refractory Hormone Receptor-Positive Breast Cancer, Desmoid Tumors, Gynecologic Tumors, or Other Hormone Receptor-Positive Solid Tumors


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Hormone Receptor-Positive Breast, Gynecologic, Desmoid, Hormone Receptor-Positive Neoplasms

Thank you

Trial Information

Phase I Trial of Z-Endoxifen in Adults With Refractory Hormone Receptor-Positive Breast Cancer, Desmoid Tumors, Gynecologic Tumors, or Other 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:

- 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 administered on a daily
schedule.

- Determine the pharmacokinetics of oral Z-endoxifen.

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

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. Six additional patients will
be entered at the MTD to assess pharmacodynamics.

- 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.

A) Z-Endoxifen (Z-Endoxifen HCl) will be given orally once a day on a continuous schedule
in 28-day cycles.

B) Blood and urine samples for PK will be collected from all patients during cycle 1 only.
Blood samples will be collected on days 1 and 28 before drug administration and at the
following times after administering Z-endoxifen: 0.5, 1, 2, 3, 4, 6, 8, and 24 (before next
dose) hours. Urine will be collected for 24 hours after dosing on day 1.

C) Tumor biopsies collected at baseline and at the end of cycle 1 (+/- 2 days). Tumor
biopsies are optional for patients enrolled in the dose escalation phase and in the
6-patient expansion cohort at the MTD.

Dose Escalation

Dose -Level Dose

Dose1-20 mg/day

Dose2-40 mg/day

Dose3-60 mg/day

Dose4-100 mg/day

Dose5-200 mg/day

Dose6-300 mg/day

Dose7-500 mg/day

Dose8-800 mg/day

Dose9-1000 mg/day

Inclusion Criteria


- 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 an aromatase inhibitor (if post-menopausal) 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.

Patients with hypertension not controlled by medical therapy (hypertension defined as
systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg despite optimal
medical management).

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Principal Investigator

Shivaani Kummar, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

110061

NCT ID:

NCT01273168

Start Date:

December 2010

Completion Date:

Related Keywords:

  • Hormone Receptor-Positive Breast
  • Gynecologic
  • Desmoid
  • Hormone Receptor-Positive Neoplasms
  • Pharmacokinetics
  • Advanced Cancer
  • Cytochrome P 450
  • Selective Estrogen Receptor Modulator
  • Tamoxifen Metabolite
  • Gynecologic Cancer
  • Breast Cancer
  • Desmoid Tumor
  • Endometrial Cancer
  • Ovarian Cancer
  • Uterine Cancer
  • Fallopian Tube Cancer
  • Peritoneal Cancer
  • Breast Neoplasms
  • Neoplasms
  • Fibromatosis, Aggressive

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892