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
- 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
- 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
- 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
- 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.
- 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
- Patients in the 6-patient expansion cohort at the MTD will be asked to undergo optional
tumor biopsies for research purposes.
- 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 -Level Dose
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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.
Shivaani Kummar, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|