seclidemstat (SP-2577) 在复发/难治性尤文肉瘤患者中的 1 期试验。,Journal of Clinical Oncology

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seclidemstat (SP-2577) 在复发/难治性尤文肉瘤患者中的 1 期试验。
Journal of Clinical Oncology ( IF 42.1 ) Pub Date : 2021-05-20 , DOI: 10.1200/jco.2021.39.15_suppl.11514
Damon R. Reed ₁ , Sant P. Chawla ₂ , Bhuvana Setty ₃ , Leo Mascarenhas ₄ , Paul A. Meyers ₅ , Jonathan Metts ₆ , Douglas James Harrison ₇ , David Loeb ₈ , Brian D. Crompton ₉ , David S. Wages ₁₀ , David D. Stenehjem ₁₁ , Daniela Y. Santiesteban ₁₂ , Nadeem Q. Mirza ₁₂ , Steven G. DuBois ₉

Affiliation

11514 背景：尤文肉瘤 (ES) 是一种罕见的骨和软组织肉瘤，主要见于青少年和年轻人，其特征是染色体易位导致融合癌蛋白。赖氨酸特异性去甲基化酶 1 (LSD1) 已被证明与融合癌蛋白相关并促进致癌转录活性，使 LSD1 成为 ES 治疗的有吸引力的靶标。Seclidemstat 是一种新型、选择性、可逆的口服 LSD1 抑制剂，能够抑制 LSD1 的催化和支架功能。这是专门针对 ES 的 1 期试验中 LSD1 抑制剂的第一份报告。方法：SALA-002-EW16 是单药 seclidemstat 在复发或难治性 (R/R) ES 患者 (pts) 中的 1 期试验。本报告描述了完成的单药剂量递增。积分 > 12 岁的患者在指定剂量水平的禁食条件下，在 28 天的周期中每天两次口服 SP-2577。主要目标是安全性和耐受性。次要目标包括确定最大耐受剂量 (MTD)、推荐的第 2 期剂量 (RP2D)、初步疗效、药代动力学和药效学。结果：截至 2020 年 12 月 30 日，27 名 R/R ES 患者入组。患者在 75 (n = 1)、150 (n = 2)、300 (n = 4)、600 (n = 6)、900 (n = 8) 或 1200 mg PO BID 时接受递增剂量的 SP-2577 ( n = 6)。中位年龄为 25 岁（范围 15-68 岁），63% 为男性，患者接受过中位数为 3 次（范围 2-12）的既往全身治疗。没有与治疗相关的死亡。最常见 (> 5%) 的 3 级治疗相关不良事件 (TRAE) 是呕吐 (15%)、腹痛 (11%) 和低钾血症 (11%)。一名患有 3 级胰腺炎的患者（4%）报告了脂肪酶升高的 4 级 AE。所有剩余的 3 级 TRAE，包括血液学 TRAE，均仅在 1 例中报告。4 名患者因 AE（体重减轻、胰腺炎、呕吐、腹痛）而停止研究。三名患者减少了剂量。第一个周期的剂量限制性毒性是在 1200 mg BID 时在 2 名患者中观察到的胃肠道相关 AE。因此，MTD/RP2D 被确定为 900 mg BID。峰值血浆浓度出现在给药后中位 4 小时 (h)，中位终末半衰期为 6 小时；通过 900 mg BID，暴露与剂量成正比。1 例 600 mg BID 的患者从 C2 末期开始减少靶病灶，并在 C4 和 C6 末期进一步缩小靶病灶（最大 76% 的肿瘤缩小），同时在 C2 结束时出现新的非靶病灶。在 C2 结束时可评估反应的患者（12 位患者）中，另外两名患者（16.7%）在 600 mg BID 和 900 mg BID 时疾病总体稳定。结论： Seclidemstat 具有可控的安全性，在经过大量预处理的复发/难治性 ES 患者中具有初步的概念验证活性。这些数据支持 seclidemstat 计划的第 2 阶段扩展，作为单一药物，并与 ES 和其他具有相似易位的肉瘤的化学疗法相结合。临床试验资料：NCT03600649。7%) 在 600 mg BID 和 900 mg BID 时疾病总体稳定。结论： Seclidemstat 具有可控的安全性，在经过大量预处理的复发/难治性 ES 患者中具有初步的概念验证活性。这些数据支持 seclidemstat 计划的第 2 阶段扩展，作为单一药物，并与 ES 和其他具有相似易位的肉瘤的化学疗法相结合。临床试验资料：NCT03600649。7%) 在 600 mg BID 和 900 mg BID 时疾病总体稳定。结论： Seclidemstat 具有可控的安全性，在经过大量预处理的复发/难治性 ES 患者中具有初步的概念验证活性。这些数据支持 seclidemstat 计划的第 2 阶段扩展，作为单一药物，并与 ES 和其他具有相似易位的肉瘤的化学疗法相结合。临床试验资料：NCT03600649。

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Phase 1 trial of seclidemstat (SP-2577) in patients with relapsed/refractory Ewing sarcoma.

11514 Background: Ewing sarcoma (ES), a rare bone and soft tissue sarcoma mainly of adolescents and young adults, is characterized by a chromosomal translocation resulting in a fusion oncoprotein. Lysine specific demethylase 1 (LSD1) has been shown to associate with the fusion oncoprotein and promote oncogenic transcriptional activity making LSD1 an attractive target for ES treatment. Seclidemstat is a novel, selective, reversible oral LSD1 inhibitor capable of inhibiting both LSD1’s catalytic and scaffolding functions. This is the first report of an LSD1 inhibitor in a Phase 1 trial focused exclusively on ES. Methods: SALA-002-EW16 is a Phase 1 trial of single agent seclidemstat in patients (pts) with relapsed or refractory (R/R) ES. This report describes the completed monotherapy dose escalation. Pts > 12 years received oral SP-2577 twice daily in 28-day cycles under fasting conditions at the assigned dose level. The primary objective was safety and tolerability. Secondary objectives include to determine maximum-tolerated dose (MTD), recommended Phase 2 dose (RP2D), preliminary efficacy, pharmacokinetics, and pharmacodynamics. Results: As of December 30, 2020, 27 pts with R/R ES were enrolled. Pts received escalating doses of SP-2577 at 75 (n = 1), 150 (n = 2), 300 (n = 4), 600 (n = 6), 900 (n = 8), or 1200 mg PO BID (n = 6). The median age was 25 years (range 15–68), 63% were male, and pts had received a median of 3 (range 2–12) prior systemic therapies. There were no treatment-related deaths. The most common ( > 5%) grade 3 treatment-related adverse events (TRAEs) were vomiting (15%), abdominal pain (11%), and hypokalemia (11%). One pt (4%) with grade 3 pancreatitis reported a grade 4 AE of elevated lipase. All remaining grade 3 TRAEs, including hematological TRAEs, were reported in only one pt each. Four pts discontinued study for an AE (weight loss, pancreatitis, vomiting, abdominal pain). Three pts had a dose reduction. The first cycle dose-limiting toxicities were gastrointestinal-related AEs observed in 2 pts at 1200 mg BID. Thus, the MTD/RP2D was established as 900 mg BID. Peak plasma concentrations occurred at a median of 4 hours (h) post-dose and median terminal half-life was 6 h; exposure was dose proportional through 900 mg BID. One pt at 600 mg BID achieved a reduction in target lesions starting at end of C2 with further target lesion tumor shrinkage through end of C4 and C6 (maximum 76% tumor shrinkage) with coincident new non-target lesion appearance at end of C2. Of pts evaluable for response at the end of C2 (12 pts), two additional pts (16.7%) at 600 mg BID and 900 mg BID had overall stable disease. Conclusions: Seclidemstat has a manageable safety profile with proof-of-concept preliminary activity in heavily pretreated pts with relapsed/refractory ES. These data support the planned Phase 2 expansion of seclidemstat as single agent and in combination with chemotherapy in ES and other sarcomas that share similar translocations. Clinical trial information: NCT03600649.

更新日期：2021-05-20

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