Uveal melanoma (UM) is associated with poor outcomes in the metastatic setting and harbors activating mutations resulting in upregulation of MAPK signaling in almost all cases. The efficacy of selumetinib, an oral allosteric inhibitor of MEK1/2, was limited when administered at a continual dosing schedule of 75 mg BID. Preclinical studies demonstrate that intermittent MEK inhibition reduces compensatory pathway activation and promotes T cell activation. We hypothesized that intermittent dosing of selumetinib would reduce toxicity, allow for the administration of increased doses, and achieve more complete pathway inhibition, thus resulting in improved antitumor activity.

We conducted a phase Ib trial of selumetinib using an intermittent dosing schedule in patients with metastatic UM. The primary objective was to estimate the maximum tolerated dose (MTD) and assess safety and tolerability. Secondary objectives included assessment of the overall response rate (RR), progression-free survival (PFS) and overall survival (OS). Tumor biopsies were collected at baseline, on day 3 (on treatment), and between days 11-14 (off treatment) from 9 patients for pharmacodynamic (PD) assessments.

29 patients were enrolled and received at least one dose of selumetinib across 4 dose levels (DL; DL1: 100 mg BID; DL2: 125 mg BID; DL3: 150 mg BID; DL4: 175 mg BID). All patients experienced a treatment-related adverse event (TRAE), with 5/29 (17%) developing a grade 3 or higher TRAE. Five dose limiting toxicities (DLT) were observed: 2/20 in DL2, 2/5 in DL3, 1/1 in DL4. The estimated MTD was 150 mg BID (DL3), with an estimated probability of toxicity of 29% (90% probability interval 16%-44%). No responses were observed; 11/29 patients achieved a best response of stable disease (SD). The median PFS and OS were 1.8 months (95% CI 1.7, 4.5) and 7.1 months (95% CI 5.3, 11.5). PD analysis demonstrated at least partial pathway inhibition in all samples at day 3, with reactivation between days 11-14 in 7 of those cases.

We identified 150 mg BID as the MTD of intermittent selumetinib, representing a 100% increase over the continuous dose MTD (75 mg BID). However, no significant clinical efficacy was observed using this dosing schedule.

葡萄膜黑色素瘤 (UM) 与转移环境中的不良结果相关，并且在几乎所有情况下都存在导致 MAPK 信号上调的激活突变。selumetinib 是一种口服 MEK1/2 变构抑制剂，当以 75 mg BID 的连续给药方案给药时，其疗效有限。临床前研究表明，间歇性抑制 MEK 可减少代偿通路激活并促进 T 细胞激活。我们假设 selumetinib 的间歇给药会降低毒性，允许增加剂量，并实现更完全的通路抑制，从而提高抗肿瘤活性。

我们在转移性 UM 患者中使用间歇给药方案进行了 selumetinib 的 Ib 期试验。主要目标是估计最大耐受剂量 (MTD) 并评估安全性和耐受性。次要目标包括评估总反应率 (RR)、无进展生存期 (PFS) 和总生存期 (OS)。在基线、第 3 天（治疗期间）和第 11-14 天（停止治疗）期间收集了 9 名患者的肿瘤活检，用于药效学 (PD) 评估。

29 名患者入组并在 4 个剂量水平（DL；DL1：100 mg BID；DL2：125 mg BID；DL3：150 mg BID；DL4：175 mg BID）中接受至少一剂司美替尼。所有患者都经历了与治疗相关的不良事件 (TRAE)，其中 5/29 (17%) 发生了 3 级或更高级别的 TRAE。观察到五种剂量限制性毒性 (DLT)：DL2 为 2/20，DL3 为 2/5，DL4 为 1/1。估计的 MTD 为 150 mg BID (DL3)，估计的毒性概率为 29%（90% 概率区间 16%-44%）。没有观察到反应；11/29 名患者达到疾病稳定 (SD) 的最佳反应。中位 PFS 和 OS 分别为 1.8 个月（95% CI 1.7, 4.5）和 7.1 个月（95% CI 5.3, 11.5）。PD 分析表明在第 3 天所有样品中至少存在部分通路抑制，其中 7 个在第 11-14 天之间重新激活。

我们将 150 mg BID 确定为间歇性 selumetinib 的 MTD，表示比连续剂量 MTD（75 mg BID）增加 100%。然而，使用该给药方案未观察到显着的临床疗效。