Mahr, MA

Abstract Background: AI's are more effective than TAM in ER+ breast cancer. In AI refractory MBC, the response rate to TAM is 0% (Osborne 2011). Z-Endx is an active metabolite of TAM and among TAM treated women in the adjuvant and metastatic settings, reduced CYP2D6 metabolism and low Endx concentrations (Css <20 nM) have been associated with increased likelihood of disease recurrence. Preclinical studies have demonstrated greater Z-Endx exposure and anti-tumor activity with oral Z-Endx compared to equivalent doses of oral TAM (Reid 2014) Methods: We conducted a phase I trial to determine the maximum-tolerated dose (MTD) and evaluate the toxicities, clinical activity, and pharmacokinetics (PK) of Z-Endx in patients (pts) with ER+, AI refractory MBC. Unlimited prior endocrine regimens were allowed. An accelerated titration schedule was applied (2 pts/dose level) until moderate toxicity or DLT, followed by a 3+3 design and then to expansion cohorts (40, 80, and 100 mg/day). Z-Endx was administered orally once daily (28 day cycle). Eye exams were performed at baseline, and end of cycles 2 and 6. PK was performed during cycle 1 and prior to subsequent cycles. For pts in the expansion cohorts, tumor biopsies were obtained at baseline for DNA sequencing (Foundation Medicine). Plasma cholesterol levels were obtained at baseline and after 1 cycle. Results: From March 2011 to Dec 2014, 41 pts (38 evaluable), median age 60, received Z-Endx once daily encompassing 7 dose levels (20-160 mg/daily). The median number of prior hormonal regimens was 2 and 3 for the dose escalation and expansion cohorts, respectively. Dose escalation was stopped at 160 mg/day given MTD not reached and attainment of mean Endx Css of 3.6 uM. Cycle 1 DLT (PE) was observed in one patient (60 mg). No eye toxicity was observed. PK demonstrated mean Endx Css of > 1 uM at all dose levels ≥ 40 mg/day. Antitumor activity was observed at multiple dose levels including 3 confirmed partial responses and an additional 7 with stable disease for ≥6 cycles. Of these 10 pts, 9 had prior progression on both AI and fulvestrant and 3 additionally on TAM. After 1 cycle, total and LDL cholesterol decreased > 20 points in 54% and 40% of pts, respectively. Tumor sequencing in the expansion cohorts (n=14) did not identify ESR1 mutations; however, ESR1 amplification was identified in 1 pt with prolonged stable disease (>200 days). Of 6 pts with rapid progression (≤2 cycles), 4/6 had either CCND1 amplification (n=1) or at least one of the following activating mutations: ERBB2 L755S (n=1), AKT1 E17K (n=1), MTOR E1799K (n=1). Conclusions: The direct administration of Z-END provides substantial drug exposure, acceptable toxicity, and "proof of principle" antitumor activity in endocrine resistant MBC. While the MTD was not determined, the goal of achieving Endx Css concentrations of > 1 uM was achieved. Tumor sequencing identified pts with predicted and confirmed endocrine resistance. A randomized phase II comparing endoxifen (80 mg/day) with TAM in AI refractory MBC was recently activated (NCT02311933). Supported in part by CA 133049, CA186686, CA15083, CA116201, and CA15083. Citation Format: Goetz MP, Suman VJ, Reid JM, Northfelt DW, Mahr MA, Dockter T, Kuffel M, Buhrow SA, Safgren SL, McGovern RM, Collins JM, Streicher H, Hawse JR, Haddad TC, Erlichman C, Ames MM, Ingle JN. Final results of 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). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD2-03.

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 > 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 >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 > 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.