Purpose: High grade gliomas (HGGs) carry a poor prognosis, with glioblastoma accounting for almost 50% of primary brain malignancies in the elderly. Unfortunately, despite the use of multiple treatment modalities, the prognosis remains poor in this population. Our pre-clinical studies suggest that the presence of aromatase expression, encoded by CYP19A1, is significantly upregulated in HGGs. Remarkably, we find that letrozole (LTZ), an FDA approved aromatase inhibitor, has marked activity against HGGs. Methods: We conducted a phase 0/I single center clinical trial (NCT03122197) to assess the tumoral availability, pharmacokinetics (PK), safety and tolerability of LTZ in recurrent HGG patients. Planned dose cohorts included 2.5, 5, 10, 12.5, 15, 17.5 and 20 mg of LTZ administered daily pre- and post-surgery or biopsy. Tumor samples were assayed for LTZ content and relevant biomarkers. The Recommended Phase 2 Dose (R2PD) was determined as the dose that resulted in predicted steady state tumoral extracellular fluid (ECF) (Css,ecf) > 2 µM and did not result in ≥ 33% dose limiting adverse events (AEs) assessed using CTCAE v5.0. Results: Twenty-one patients were enrolled. Common LTZ related AEs included fatigue, nausea, musculoskeletal, anxiety and dysphoric mood. No DLTs were observed. The 15 mg dose achieved a Css,ecf of 3.6 +/- 0.59 µM. LTZ caused dose-dependent inhibition of estradiol synthesis and modulated DNA damage pathways in tumor tissues as evident using RNA-seq analysis. Conclusion: Based on safety, brain tumoral PK, and mechanistic data, 15 mg daily is identified as the RP2D for future trials.

中文翻译：

---

来曲唑联合标准疗法治疗复发性高级别胶质瘤的 0/1 期药代动力学和药效学以及安全性和耐受性研究

目的：高级别胶质瘤 (HGG) 预后较差，其中胶质母细胞瘤几乎占老年人原发性脑恶性肿瘤的 50%。不幸的是，尽管使用了多种治疗方式，该人群的预后仍然很差。我们的临床前研究表明，由 CYP19A1 编码的芳香酶表达在 HGG 中显着上调。值得注意的是，我们发现 FDA 批准的芳香酶抑制剂来曲唑 (LTZ) 对 HGG 具有显着的活性。方法：我们进行了一项 0/I 期单中心临床试验 (NCT03122197)，以评估 LTZ 在复发性 HGG 患者中的肿瘤可用性、药代动力学 (PK)、安全性和耐受性。计划剂量组包括每天在手术或活检前和术后施用 2.5、5、10、12.5、15、17.5 和 20 mg LTZ。分析肿瘤样本的 LTZ 含量和相关生物标志物。推荐的2期剂量(R2PD)被确定为导致预测的稳态肿瘤细胞外液(ECF)(Css，ecf)＞1的剂量。 2 µM，并没有导致使用 CTCAE v5.0 评估的 ≥ 33% 剂量限制性不良事件 (AE)。结果：21 名患者入组。常见的 LTZ 相关 AE 包括疲劳、恶心、肌肉骨骼、焦虑和烦躁情绪。没有观察到 DLT。 15 mg 剂量的 Css,ecf 为 3.6 +/- 0.59 µM。 RNA-seq 分析表明，LTZ 会导致雌二醇合成的剂量依赖性抑制，并调节肿瘤组织中的 DNA 损伤途径。结论：基于安全性、脑肿瘤 PK 和机制数据，每日 15 mg 被确定为未来试验的 RP2D。