METHODS: This phase 1b, open-label, dose-escalation study (NCT03745989) enrolled adults with histologically/cytologically documented, locally advanced/metastatic solid tumors. MK-8353/selumetinib dose combinations were intended to be investigated in sequence: 50/25, 100/50, 150/75, 200/75, 200/100, and 250/100. Each agent was administered orally BID 4 days on/3 days off in repeating cycles every 21 days. Primary objectives were safety and tolerability and to establish preliminary recommended phase 2 doses for combination therapy.
RESULTS: Thirty patients were enrolled. Median (range) age was 61.5 (26-78) years and 93% had received previous cancer therapy. Among 28 patients in the dose-limiting toxicities [DLT]-evaluable population, 8 experienced DLTs: 1/11 (9%) in the MK-8353/selumetinib 100/50-mg dose level experienced a grade 3 DLT (urticaria), and 7/14 (50%) in the 150/75-mg dose level experienced grade 2/3 DLTs (n = 2 each of blurred vision, retinal detachment, vomiting; n = 1 each of diarrhea, macular edema, nausea, retinopathy). The DLT rate in the latter dose level exceeded the prespecified target DLT rate (~30%). Twenty-six patients (87%) experienced treatment-related adverse events (grade 3, 30%; no grade 4/5), most commonly diarrhea (67%), nausea (37%), and acneiform dermatitis (33%). Three patients (10%) experienced treatment-related adverse events leading to treatment discontinuation. Best response was stable disease in 14 patients (n = 10 with MK-8353/selumetinib 150/75 mg).
CONCLUSIONS: MK-8353/selumetinib 50/25 mg and 100/50 mg had acceptable safety and tolerability, whereas 150/75 mg was not tolerable. No responses were observed.
方法:此阶段1b,开放标签,剂量递增研究(NCT03745989)纳入有组织学/细胞学记录的成人,局部晚期/转移性实体瘤。MK-8353/司美替尼剂量组合旨在按以下顺序进行研究:50/25、100/50、150/75、200/75、200/100和250/100。每21天以重复周期口服BID给药4天/3天。主要目标是安全性和耐受性,并建立联合治疗的初步推荐2期剂量。
结果:纳入30例患者。中位(范围)年龄为61.5(26-78)岁,93%曾接受过癌症治疗。在剂量限制性毒性[DLT]可评估人群中的28名患者中,8个有经验的DLT:MK-8353/selumetinib100/50-mg剂量水平的1/11(9%)经历了3级DLT(荨麻疹),和7/14(50%)在150/75毫克剂量水平经历2/3级DLT(n=2每个视力模糊,视网膜脱离,呕吐;腹泻各n=1,黄斑水肿,恶心,视网膜病变)。后一剂量水平的DLT率超过预定的目标DLT率(~30%)。26例患者(87%)经历了与治疗相关的不良事件(3级,30%;无4/5级)。最常见的腹泻(67%),恶心(37%),和痤疮样皮炎(33%)。三名患者(10%)经历了治疗相关的不良事件,导致治疗中止。最佳反应是14例患者的疾病稳定(n=10,MK-8353/selumetinib150/75mg)。
结论:MK-8353/司美替尼50/25mg和100/50mg具有可接受的安全性和耐受性,而150/75mg则不能耐受。没有观察到反应。