Angevin Eric, Isambert Nicolas, Trillet-Lenoir Véronique, You Benoit, Alexandre Jérôme, Zalcman Gérard, Vielh Philippe, Farace Françoise, Valleix Fanny, Podoll Thomas, Kuramochi Yu, Miyashita Itaru, Hosono Osamu, Dang Nam H, Ohnuma Kei, Yamada Taketo, Kaneko Yutaro, Morimoto Chikao
Gustave Roussy, Université Paris-Saclay, Drug Development Department (DITEP), Villejuif, France.
Centre Georges-François Leclerc, Unité de Phases Précoces, Dijon, France.
Br J Cancer. 2017 Apr 25;116(9):1126-1134. doi: 10.1038/bjc.2017.62. Epub 2017 Mar 14.
YS110 is a humanised IgG1 monoclonal antibody with high affinity to the CD26 antigen. YS110 demonstrated preclinical anti-tumour effects without significant side effects.
This FIH study was designed to determine the maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D) to assess the tolerance, pharmacokinetics (PK) and pharmacodynamics profiles of YS110 and preliminary efficacy. YS110 were initially administered intravenously once every 2 weeks (Q2W) for three doses and then, based on PK data, once every week (Q1W) for five doses in patients with CD26-expressing solid tumours.
Thirty-three patients (22 mesothelioma) received a median of 3 (range 1-30) YS110 infusions across six dose levels (0.1-6 mg kg). MTD was not reached and two dose-limiting toxicities (infusion hypersensitivity reactions) led to the institution of a systemic premedication. Low-grade asthenia (30.3%), hypersensitivity (27.3%), nausea (15.2%), flushing (15.2%), chills (12.1%) and pyrexia (12.1%) were reported as ADRs. Pharmacokinetic parameters (AUC and C) increased in proportion with the dose. sCD26/DPPIV assays indicated CD26 modulation. Prolonged stable diseases were observed in 13 out of 26 evaluable patients.
YS110 is well tolerated up to 6 mg kg Q1W, which has been defined as the RP2D, with encouraging prolonged disease stabilisations observed in a number of patients with advanced/refractory mesothelioma.
YS110是一种对CD26抗原具有高亲和力的人源化IgG1单克隆抗体。YS110在临床前研究中显示出抗肿瘤作用且无明显副作用。
这项首次人体研究旨在确定最大耐受剂量（MTD）和推荐的2期剂量（RP2D），以评估YS110的耐受性、药代动力学（PK）和药效学特征以及初步疗效。对于表达CD26的实体瘤患者，YS110最初每2周静脉注射一次（Q2W），共注射三剂，然后根据PK数据，每1周注射一次（Q1W），共注射五剂。
33例患者（22例间皮瘤）在六个剂量水平（0.1 - 6mg/kg）接受了中位数为3次（范围1 - 30次）的YS110输注。未达到MTD，两例剂量限制性毒性（输液过敏反应）导致采用全身性预处理。报告的不良反应包括轻度乏力（30.3%）、过敏（27.3%）、恶心（15.2%）、潮红（15.2%）、寒战（12.1%）和发热（12.1%）。药代动力学参数（AUC和C）与剂量成比例增加。sCD26/DPPIV检测表明CD26受到调节。在26例可评估患者中的13例观察到疾病长期稳定。
YS110在高达6mg/kg Q1W的剂量下耐受性良好，该剂量已被定义为RP2D，在一些晚期/难治性间皮瘤患者中观察到令人鼓舞的疾病长期稳定情况。
