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Abstract：
OBJECTIVE: We evaluated MK-8353 (small molecule inhibitor of extracellular signal-regulated kinase 1/2) plus selumetinib (mitogen-activated extracellular signal-regulated kinase 1/2 inhibitor) in patients with advanced solid tumors.
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.
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.
摘要：
目的：我们评估了MK-8353（细胞外信号调节激酶1/2的小分子抑制剂）联合司美替尼（丝裂原激活的细胞外信号调节激酶1/2抑制剂）治疗晚期实体瘤的疗效。
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。
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。
