Abstract 4631: Pharmacokinetics and in vivo metabolism of Z-endoxifen: Results from two phase I studies in women with ER+ breast cancer, gynecologic malignancies and desmoids
Authors: Reid Joel M. , Goetz Matthew P. , Kumar Shivaani , McGovern Renee M. , Buhrow Sarah A. , Safgren Stephanie L. , Suman Vera J. , Docktor Travis J. , Erlichman Charles , Streicher Howard , Doroshow James H. , Collins Jerry , Ames Matthew M. 
Published: May 2015

Abstract
Background: Breast cancer recurrence has been shown to differ based upon CYP2D6 genotype and endoxifen (Endx) exposure following treatment with tamoxifen (TAM) in the adjuvant setting. The average Endx Css is 29 nM (range, 2-80 nM) in TAM treated patients at a dose of 20 mg/day. Administration of Endx itself to patients is predicted to provide adequate, consistent, active drug levels in all treated patients, resulting in clinical benefit. As part of two phase 1 trials of oral Endx to determine the safety, tolerability, and MTD, we characterized the pharmacokinetics and in vivo metabolism of Endx.
Methods: Patients were given escalating daily oral doses of Endx (28 day cycle) over the dose range of 20 - 160 mg/day in Phase I trials at the Mayo Clinic and NCI. Pharmacokinetics sampling was performed on days 1, 7, 14 and 28, and prior to subsequent cycles. Endx plasma concentrations and metabolite profiles were determined by HPLC and LC/MS/MS.
Results: 44 patients with ECOG PS 0-1 have been enrolled to date encompassing 8 dose levels in the Mayo (25 women with AI refractory MBC; median age 58 yrs, range 41-83 yrs) and NCI (19 women with ovary (9), breast (4), desmoid (2), fallopian tube (2), endometrial cancer (2); median age 64 yrs, range 43-75 yrs) studies. Day 1 Endx peak concentrations (Cmax) were reached 4h after the Endx oral dose and mean values of Cmax, C24h, and AUC0-24h increased in proportion to dose. Css was achieved on day 7 and 3.5-fold accumulation (t1/2= 50.5 h) was observed on day 28. At the starting dose ( 20 mg/day) and highest dose level (160 mg/day), Endx Css values of 146 ng/ml (390 nM) and 1950 ng/ml (5200 nM), respectively, were achieved and maintained throughout the 28-day treatment. Endx Css values remained unchanged following continuous dosing for 8-10 months. The mean apparent steady-state clearance was 6.2 L/h. We also characterized the Endx metabolite profile in patient plasma and urine. Metabolites detected in plasma include nor-Endx, N-hydroxy-Endx, Endx-catechol, methoxy-Endx catechol, and Endx-glucuronide, and appear in amounts much lower compared to Endx. Like the parent drug, metabolites accumulated in plasma over the 28-day cycle. Characterization of the pharmacokinetics of Nor-Endx, a putative aromatase inhibitor, is ongoing and will be presented.
Conclusion: In these ongoing Phase I studies, daily administration of Endx is well tolerated with Css consistently above those obtained following administration of standard dose tamoxifen. In the Mayo study, expansion at 20 and 100 mg/day has commenced to perform translational studies and further characterize Endx PK. In the NCI study, dose escalation continues to establish the maximum tolerated dose.
Supported in part by R01CA 133049, U01 CA69912, P30CA 15083, P50CA 116201 and NCI Contracts CM52206 and HHSN261201100014C.
Citation Format: Joel M. Reid, Matthew P. Goetz, Shivaani Kumar, Renee M. McGovern, Sarah A. Buhrow, Stephanie L. Safgren, Vera J. Suman, Travis J. Docktor, Charles Erlichman, Howard Streicher, James H. Doroshow, Jerry Collins, Matthew M. Ames. Pharmacokinetics and in vivo metabolism of Z-endoxifen: Results from two phase I studies in women with ER+ breast cancer, gynecologic malignancies and desmoids. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4631. doi:10.1158/1538-7445.AM2014-4631