3083
背景： Polycomb Repressive Complex 2 (PRC2) 通过组蛋白 H3 在赖氨酸 27 (H3K27me3) 的三甲基化来调节转录。在几种情况下，其失调和过度表达与肿瘤发生有关。MAK683 是一种有效的 PRC2 激活口服抑制剂，变构靶向 EED-H3K27me3 结合位点。方法：NCT02900651是一项正在进行的MAK683在成人晚期恶性肿瘤中的首次人体剂量递增研究。MAK683 在 28 天的治疗周期中连续禁食一次 (QD) 或每天两次 (BID)。MAK683 的药代动力学 (PK) 曲线在第 1-6 周期的第 1、8 和/或 15 天的连续血液样本中进行了评估。第 1 周期的 MAK683 药效学活性（通过 H3K27me3 的变化测量）在第 1、8 和 15 天通过流式细胞术在外周血单核细胞中进行评估，并在基线和第 15 天通过 H 评分在肿瘤活检中进行评估。结果：截至 2021 年 8 月 30 日，125 名患者接受了 MAK683，剂量为 10-800 mg QD 或 60-450 mg BID。MAK683 被很好地吸收，整个队列的中位 T max为 ̃1-4 小时。PK暴露（C最大值, AUC) 通常在整个剂量范围内随剂量增加而与剂量比例没有重大偏差，同时考虑到样本量和 PK 变异性。各组的表观终末半衰期（几何平均值）为 2.5-6.6 小时，并且随着时间的推移保持不变。MAK683 累积 ̃0.9-2.2 倍 (QD) 或 ̃1.3-2.0 倍 (BID) 重复给药。外周单核细胞在不同剂量下的 H3K27me3/H3 比率从基线开始显着降低。最大百分比减少与累积 MAK683 AUC 成正比，在较高的基线 H3K27me3 有更大减少的趋势。在 7/10 患有弥漫性大 B 细胞淋巴瘤 (n = 4) 或上皮样肉瘤 (n = 6) 和配对基线 - 第 15 天活检的患者中观察到 H3K27me3 H 评分从基线降低 > 40。结论： MAK683 的 PK 曲线支持晚期恶性肿瘤患者的 QD 或 BID 给药。血液单核细胞和肿瘤活检中的 H3K27me3 分析证实了MAK683的体内药效学活性。临床试验资料：NCT02900651。
"点击查看英文标题和摘要"
Pharmacokinetic and pharmacodynamic activity evaluation of MAK683, a selective oral embryonic ectoderm development (EED) inhibitor, in adults with advanced malignancies in a first-in-human study.
3083
Background: Polycomb Repressive Complex 2 (PRC2) regulates transcription via trimethylation of histone H3 at lysine 27 (H3K27me3). Its dysregulation and over-expression are associated with tumorigenesis in several conditions. MAK683 is a potent oral inhibitor of PRC2 activation, allosterically targeting the EED–H3K27me3 binding site. Methods: NCT02900651 is an ongoing first-in-human dose-escalation study of MAK683 in adults with advanced malignancies. MAK683 was administered fasted once (QD) or twice daily (BID) on a continuous schedule in 28-day treatment cycles. The pharmacokinetic (PK) profile of MAK683 was assessed in sequential blood samples on Days 1, 8 and/or 15 of Cycles 1–6. MAK683 pharmacodynamic activity in Cycle 1, measured by change in H3K27me3, was evaluated in peripheral blood monocytes on Days 1, 8, and 15 by flow cytometry and in tumor biopsies at baseline and Day 15 by H-score. Results: As of Aug 30, 2021, 125 patients had received MAK683 at doses of 10–800 mg QD or 60–450 mg BID. MAK683 was well absorbed with a median Tmax of ̃1-4 hours across cohorts. PK exposure (Cmax, AUC) increased generally with dose over the entire dose range with no major deviation from dose proportionality, taking into account the sample size and PK variability. Apparent terminal half-life (geometric mean) was 2.5–6.6 hours across cohorts and constant over time. MAK683 accumulation of ̃0.9-2.2-fold (QD) or ̃1.3-2.0-fold (BID) was seen with repeat dosing. Peripheral monocytes showed substantial on-treatment reductions from baseline in the H3K27me3/H3 ratio across doses. Maximum percentage reduction was proportional to cumulative MAK683 AUC, with a trend towards greater reductions at higher baseline H3K27me3. H3K27me3 H-score reductions from baseline > 40 were observed in 7/10 patients with diffuse large B-cell lymphoma (n = 4) or epithelioid sarcoma (n = 6) and paired baseline–Day 15 biopsies. RNA-seq characterization of biopsy samples is ongoing. Conclusions: MAK683 has a PK profile supportive of QD or BID dosing in patients with advanced malignancies. Analysis of H3K27me3 in blood monocytes and tumor biopsy confirm the in vivo pharmacodynamic activity of MAK683. Clinical trial information: NCT02900651.
京公网安备 11010802027423号