Abstract PD3-4: A first-in-human phase I study of the tamoxifen (TAM) metabolite, Z-endoxifen hydrochloride (Z-Endx) in women with aromatase inhibitor (AI) refractory metastatic breast cancer (MBC) (NCT01327781)
Authors: Goetz MP , Suman VA , Reid JR , Northfelt DW , Mahr MA , Dockter T , Haluska PJ , Kuffel M , Burhow S , Safgren S , McGovern R , Collins J , Streicher H , Hawse JR , Erlichman C , Ingle JN , Ames MM 
Published: August 2014

Abstract
Background: In AI refractory MBC, TAM anti-tumor activity is limited (median PFS 4.5 months). In patients (pts) receiving TAM in the adjuvant and metastatic setting, breast cancer recurrence has been shown to differ based upon CYP2D6 genotype and Endx exposure. In collaboration with NCI, Z-Endx (NSC #750393) was synthesized and preclinical pharmacology studies demonstrated that oral Z- Endx resulted in &gt; 20 fold Endx exposure compared to an equivalent dose of TAM and significantly greater anti-tumor activity than TAM in AI sensitive and resistant MCF7 xenografts. We conducted a phase I study of Z-Endx in women with ER+, AI refractory MBC to identify dose-limiting toxicities (DLT), a maximum tolerated dose (MTD) and a dose associated with steady state concentrations (Css) of ≥ 2 uM, based on the IC50 of recently identified Endx substrates: PKC and PI3K.
Methods: Pts were enrolled to an accelerated titration schedule (2 pts/dose level) until moderate toxicity or DLT, and then to a 3+3 design. Z-Endx was administered orally once daily (28 day cycle). Eye exams were performed at baseline, end of cycle 2, and after 6 cycles. PK was performed on days 1-2, 3, 7, 14, and 28, and prior to subsequent cycles.
Results: 23 women with AI refractory MBC (median 56 yrs, range 41-83) received Z-Endx once daily encompassing 7 dose levels (Table 1). The median number of prior chemotherapies and hormonal therapies in the metastatic setting were 2 and 2, respectively. Dose escalation continues at 160 mg/day and the MTD has yet to be determined. Cmax and AUC increased in a dose-dependent manner. A 20 and 100 mg/day dose yields Css of 0.39 and 2.48 uM, respectively. Significant anti-tumor activity was observed including 1 pt (100 mg/day) with a PR lasting 225 days; 1 pt (80 mg/day) with a 30% reduction in tumor size (PFS 169 days) and 2 pts (60 and 80 mg/day) with stable disease for &gt;270 days. No eye toxicity was observed.
Conclusions: In women with AI refractory MBC, the MTD of Z-Endx HCl has not been determined but Endx Css concentrations of &gt; 2 uM and substantial anti-tumor activity has been observed. Following completion of the 160 mg/day dose, expansion at 20 and 100 mg/day will commence to perform translational studies and further characterize Endx pk. A randomized phase II examining two different doses of Z-Endx is planned in AI refractory MBC. Supported in part by CA 133049, CA69912, CA15083, CA116201, and CA15083.
Table 1Dose Level (mg/day)Number of Treatment CyclesModerate or Severe Toxicities ReportedTumor ResponseProgression-free Survival (days)28 day Z-Endx Css (uM) 20 (n = 2)2; 3Gr 2 hot flashes (1 pt)----60; 850.39 40 (n = 2)2; 6noneStable (1 pt)61; 1670.66 60 (n = 6)1; 2; 2; 5; 8; 14Gr 4 Triglycerides (1 pt);Gr 3 thromboembolic event (1 pt); Gr 2 hot flashes, anemia, and hypoalbuminemia (1 pt)Stable (3 pts)125+; 56; 57; 132; 232; 4331.01 80 (n = 3)4; 6; 10Gr 2 hot flashesStable (3 pts)113; 169; 2961.61 100 (n = 3)1; 2; 8Gr 2 nausea (1 pt); Gr 2 irritability (1 pt)PR (1 pt)30; 56; 2252.48 120 (n = 3)1; 2; 4Gr 2 hypersomnia, paresthesia, and peripheral sensory neuropathy (1 pt)—39; 54; 1082.18 * Bold face toxicities occurred during cycle 1
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD3-4.