Burhow, Sarah A.

TPS655 Background: Early (14-28 day) on-treatment suppression of tumor proliferation during neoadjuvant endocrine therapy (NET) is strongly associated with favorable long-term outcomes in estrogen receptor–positive (ER+) HER2– breast cancer. In premenopausal women, tamoxifen with or without ovarian function suppression (OFS) results in suboptimal Ki-67 suppression compared with aromatase inhibitor + OFS. (Z)-endoxifen (ENDX), the active metabolite of tamoxifen, dually inhibits ER signaling and PKCβ1-mediated AKT activation, supporting its evaluation as an alternative NET strategy in this population. Methods: EVANGELINE (NCT05607004) is an ongoing, multicenter, open-label Phase 2 study evaluating daily 40 mg ENDX plus goserelin administered every 28 days as neoadjuvant therapy in premenopausal women with ER+/HER2–, cT2–3, cN0–1 breast cancer. The primary objective is to determine the proportion of patients with baseline Ki-67 >10% who achieve Ki-67 ≤10% after 4 weeks of therapy. A Simon two-stage design is used to test whether the Week 4 Ki-67 ≤10% rate is at least 65%, with 20 patients enrolled into the first stage and, if promising, another 25 patients enrolled into the second stage (cohort A). A parallel cohort of 20 patients with baseline Ki-67 ≤10% (cohort B) is enrolled to assess objective response rate (ORR) at 24 weeks per RECIST v1.1. Secondary objectives include examining safety and tolerability, residual cancer burden, and PEPI score. Correlative analyses include examining effect of treatment on select tumor and plasma biomarkers. Clinical trial information: NCT05607004 .

10526 Background: Pro-angiogenic factors may represent therapeutic targets in sarcoma. Preclinical studies have demonstrated a potential additive or synergistic interaction between anti-angiogenic agents and chemotherapy. The purpose of this study was to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetic (PK) and pharmacodynamics (PD) effects of PAZIT in patients with advanced sarcoma. Methods: Patients 6-30 years of age with relapsed/refractory sarcomas were eligible. In the initial dose escalation plan (A), patients received pazopanib PO (225-450 mg/m2/dose) on Days 1-21 of 21-day cycles. Pazopanib was combined with fixed doses of irinotecan (IV 50 or PO 90 mg/m2/dose) and temozolomide PO 100 mg/m2/dose on Days 1-5. Due to DLTs, an amendment was made to the dose escalation plan (B) and patients received fixed doses of pazopanib PO (225 mg/m2/dose) on Days 1-21 of 21-day cycles and reduced irinotecan doses (IV 25-37.5 or PO 45-67.5 mg/m2/dose) and temozolomide PO 100 mg/m2/dose on Days 1-5. Oral cephalosporin diarrhea prophylaxis was required. Dose escalation followed a 3+3 design. Correlative studies included PK (pazopanib, irinotecan) and PD (angiogenic factors, ctDNA) effects. Results: Sixteen patients were treated (median age 16 years, range 7-21). The dose levels in the table were evaluated. First cycle DLTs occurred at all dose levels (Table) and included diarrhea, pancreatitis, colitis, neutropenia, hypertension, deep vein thrombosis, and ALT increase. Due to excessive toxicity, an MTD could not be established. One patient with osteosarcoma had a partial response. Four patients had prolonged stable disease > 4 cycles, including 2 patients with Ewing sarcoma (5 and 6 cycles), rhabdomyosarcoma (9 cycles), and desmoplastic small round cell tumor (6 cycles). Mean±SD plasma exposures to pazopanib, irinotecan, and SN-38 in patients treated on dose level 1B (n = 4) on Day 4 were 601±83, 1.4±0.2 and 0.1±0.04 ug/mL*hr, respectively. Analyses of correlative studies are ongoing. Conclusions: Combination PAZIT therapy is not tolerable as evaluated at these doses/schedules. This study provides important toxicity data to inform future clinical trials using combination anti-angiogenic strategies in sarcoma. Clinical trial information: NCT03139331. [Table: see text]

1043 Background: In estrogen receptor (ER) positive MBC, mutations (e.g. ESR1), identified from tumor biopsies or cfDNA, confer resistance. The concordance between mutations observed in tumor and cfDNA and the implications for response to Z-endoxifen, a potent anti-estrogen, are unknown. Methods: We previously conducted a phase I trial of Z-endoxifen in endocrine refractory, ER positive MBC. Seven dose levels were considered ranging from 20 to 160 mg/day followed by expansion cohorts (EC) of 40, 80, and 100 mg/day. Pretreatment blood samples (all pts) and fresh tumor biopsies (EC) were collected prospectively. Tumor and cfDNA were evaluated by targeted NGS. Results: 41 pts (38 evaluable) were enrolled. Prior endocrine therapy included aromatase inhibitors (37/38, 97%), fulvestrant (22/38, 58%) and tamoxifen (26/38, 68%). Substantial endoxifen exposure without DLTs at doses above 80 mg/day led to a halt in dose escalation and opening of the EC. Overall clinical benefit (stable > 6 months [7 pts.] or partial response by RECIST criteria [3 pts.]) rate was 26.3% (95%CI: 13.4-43.1%). cfDNA was obtained from 36 pts and mutations were identified in 13 (36%) including ESR1 [ Y537N or D538G] (5), PIK3CA [ H1047R or E542K] (8), TP53 [ K132R, R248Q, R267Q, or H179Y] (4), AKT ( Q79K) (1), and KRAS ( G12D) (1). In 5 pts with cf ESR1 mutations, 4 had additional cfDNA mutations including PIK3CA (3), and TP53 (1). PFS was shorter in pts with cfDNA mutations relative to those without (median: 61 vs.132 days; log-rank p = 0.021). Discordance was observed between tumor and cfDNA mutations where 3/7 PIK3CA tumor mutations were detected by cfDNA, 1/2 TP53 tumor mutations were detected by cfDNA, and 0/1 AKT tumor mutations were detected by cfDNA. Conversely, 2 pts had cfDNA mutations (either ESR1, TP53 or AKT) undetected in tumor. Conclusions: The absence of cfDNA mutations in patients with endocrine resistant, MBC treated with Z-Endoxifen was associated with significantly longer PFS. Given the discordance between tumor and cfDNA sequence data, future studies must determine which approach maximizes prognosis and prediction of benefit for estrogen-targeted therapy. Clinical trial information: NCT01327781.

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.