Phase I trial of z-endoxifen with estrogen receptor imaging in adults with advanced hormone receptor-positive solid tumors including desmoid and gynecologic tumors.

Background: Differential response to tamoxifen observed in patients (pts) with hormone receptor-positive cancer may be due to variations in tamoxifen metabolism from CYP2D6 genetic polymorphisms that limit exposure to the active metabolite, zendoxifen (Z). We conducted a phase 1 clinical trial (3+3 design) with estrogen receptor imaging to determine the safety, MTD, and pharmacokinetics (PK) of oral Z. Methods: Adults with refractory gynecologic tumors, hormone-positive breast or other solid tumors, or desmoid tumors were eligible with ECOG performance status of 0-2 and adequate organ functions. Z was administered at 20, 40, 60, 100, 140, 200, 280, and 360 mg q day on a 28-day cycle. Estrogen receptor imaging with 16 alpha-[ F]-fluoro-17 betaestradiol (FES)-PET was performed before dosing and, if positive, repeated during C1W1. Results: Median age of the 40 pts enrolled was 60 (range 21-80 yr) and 90% were female. MTD was not reached up to the targeted maximum dose of 360 mg/day. Of the 38 pts evaluable for response, 2 (fallopian tube and breast) had partial responses and 9 had 6+ cycles of stable disease. Pts stayed on study for 1-47+ cycles (average, 6 cycles; median, 2.5 cycles); two pts remain on treatment. Grade 3/4 adverse events occurring in ≥5% of pts were hypertension (13%), hyponatremia (8%), hypophosphatemia (8%), neutropenia (8%), dehydration (5%), and elevated ALT (5%). Mean Z plasma levels increased linearly with administered dose. Increases were seen in mean D1 C (68.6 to 1309 ng/mL) and AUC (1084 to 20546 ng/mL-hr) between doses of 20 and 360 mg/day. The elimination t was 30.6-55.9 hr, based on the AUC accumulation ratio of 2.4-3.9 over the 28-day dosing period. FES-PET from 9 pts with FES-positive lesions demonstrated a 2%-76% reduction in average FES standard uptake values following 2-5 days of Z. Conclusions: We established a targeted maximum dose of 360 mg/day Z and evidence of antitumor activity was observed. Oral Z administration produces Z plasma exposures well above those obtained after therapeutic doses of tamoxifen.