Purpose Endoxifen is a tamoxifen metabolite with potent antiestrogenic activity. Patients and Methods We performed a phase I study of oral Z-endoxifen to determine its toxicities, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity. Eligibility included endocrine-refractory, estrogen receptor-positive metastatic breast cancer. An accelerated titration schedule was applied until moderate or dose-limiting toxicity occurred, followed by a 3+3 design and expansion at 40, 80, and 100 mg per day. Tumor DNA from serum (circulating cell free [cf); all patients] and biopsies [160 mg/day and expansion]) was sequenced. Results Of 41 enrolled patients, 38 were evaluable for MTD determination. Prior endocrine regimens during which progression occurred included aromatase inhibitor (n = 36), fulvestrant (n = 21), and tamoxifen (n = 15). Patients received endoxifen once daily at seven dose levels (20 to 160 mg). Dose escalation ceased at 160 mg per day given lack of MTD and endoxifen concentrations > 1,900 ng/mL. Endoxifen clearance was unaffected by CYP2D6 genotype. One patient (60 mg) had cycle 1 dose-limiting toxicity (pulmonary embolus). Overall clinical benefit rate (stable > 6 months [n = 7] or partial response by RECIST criteria [n = 3]) was 26.3% (95% CI, 13.4% to 43.1%) including prior tamoxifen progression (n = 3). cfDNA mutations were observed in 13 patients ( PIK3CA [n = 8], ESR1 [n = 5], TP53 [n = 4], and AKT [n = 1]) with shorter progression-free survival ( v those without cfDNA mutations; median, 61 v 132 days; log-rank P = .046). Clinical benefit was observed in those with ESR1 amplification (tumor; 80 mg/day) and ESR1 mutation (cfDNA; 160 mg/day). Comparing tumor biopsies and cfDNA, some mutations ( PIK3CA, TP53, and AKT) were undetected by cfDNA, whereas cfDNA mutations ( ESR1, TP53, and AKT) were undetected by biopsy. Conclusion In endocrine-refractory metastatic breast cancer, Z-endoxifen provides substantial drug exposure unaffected by CYP2D6 metabolism, acceptable toxicity, and promising antitumor activity.

中文翻译：

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他莫昔芬代谢物 Z-Endoxifen 在内分泌难治性转移性乳腺癌女性中的首次人体 I 期研究

用途 Endoxifen 是一种具有强效抗雌激素活性的他莫昔芬代谢物。患者和方法 我们进行了一项口服 Z-endoxifen 的 I 期研究，以确定其毒性、最大耐受剂量 (MTD)、药代动力学和临床活性。资格包括内分泌难治性、雌激素受体阳性转移性乳腺癌。应用加速滴定计划，直到出现中度或剂量限制性毒性，然后采用 3+3 设计并扩展为每天 40、80 和 100 mg。来自血清的肿瘤 DNA（无循环细胞 [cf]）；所有患者]和活检[160 mg/天和扩展]）进行了测序。结果 41 名登记患者中，38 名可评估 MTD 测定。发生进展的既往内分泌治疗方案包括芳香化酶抑制剂 (n = 36)、氟维司群 (n = 21) 和他莫昔芬 (n = 15)。患者每天接受 endoxifen 一次，剂量为 7 个剂量水平（20 至 160 mg）。鉴于缺乏 MTD 和 endoxifen 浓度 > 1,900 ng/mL，剂量递增在每天 160 mg 时停止。Endoxifen 清除率不受 CYP2D6 基因型的影响。一名患者 (60 mg) 在第 1 周期出现剂量限制性毒性（肺栓塞）。总体临床获益率（稳定 > 6 个月 [n = 7] 或根据 RECIST 标准 [n = 3] 部分缓解）为 26.3%（95% CI，13.4% 至 43.1%），包括既往他莫昔芬进展（n = 3）。在 13 名无进展生存期较短的患者（PIK3CA [n = 8]、ESR1 [n = 5]、TP53 [n = 4] 和 AKT [n = 1]）中观察到 cfDNA 突变（v 无 cfDNA 突变的患者；中位数，61 对 132 天；对数秩 P = .046）。在 ESR1 扩增（肿瘤；80 mg/天）和 ESR1 突变（cfDNA；160 mg/天）的患者中观察到临床获益。比较肿瘤活检和 cfDNA，cfDNA 未检测到一些突变（PIK3CA、TP53 和 AKT），而活检未检测到 cfDNA 突变（ESR1、TP53 和 AKT）。结论 在内分泌难治性转移性乳腺癌中，Z-endoxifen 提供了不受 CYP2D6 代谢影响的大量药物暴露、可接受的毒性和有前途的抗肿瘤活性。