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-\[18F\]-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 \[18F\]FES uptake using PET/CT in hormone receptor-positive tumors before and after treatment with oral Z endoxifen HCl. 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.