■葡萄膜黑色素瘤(UM)与转移环境中的不良结局有关,并且在几乎所有情况下都存在激活突变,导致MAPK信号传导上调。司米替尼的疗效,MEK1/2的口服变构抑制剂在75mgBID的连续给药方案中受到限制.临床前研究表明,间歇性MEK抑制减少代偿途径活化并促进T细胞活化。我们假设间歇性给药司美替尼可以降低毒性,允许增加剂量的给药,并实现更完整的通路抑制,从而导致提高的抗肿瘤活性。
■我们在转移性UM患者中使用间歇给药方案进行了司美替尼的Ib期试验。主要目的是评估最大耐受剂量(MTD)并评估安全性和耐受性。次要目标包括评估总体反应率(RR),无进展生存期(PFS)和总生存期(OS)。在基线时收集肿瘤活检,在第3天(治疗),并在第11-14天(停止治疗)之间对9名患者进行药效学(PD)评估。
■29名患者入选,并在4个剂量水平(DL;DL1:100mgBID;DL2:125mgBID;DL3:150mgBID;DL4:175mgBID)接受至少一剂司美替尼。所有患者均出现治疗相关不良事件(TRAE),5/29(17%)发展为3级或更高的TRAE。观察到五种剂量限制性毒性(DLT):在DL2中为2/20,在DL3中为2/5,在DL4中为1/1。估计的MTD为150毫克BID(DL3),估计毒性概率为29%(90%概率区间为16%-44%)。未观察到反应;11/29患者达到稳定疾病(SD)的最佳反应。中位PFS和OS分别为1.8个月(95%CI1.7,4.5)和7.1个月(95%CI5.3,11.5)。PD分析证实在第3天所有样品中至少部分途径抑制,其中7个病例在第11-14天之间重新激活。
■我们确定了150mgBID作为间歇性司米替尼的MTD,表示比连续剂量MTD(75mgBID)增加100%。然而,使用该给药方案未观察到显著的临床疗效.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.