First-in-human phase 1 of YS110, a monoclonal antibody directed against CD26 in advanced CD26-expressing cancers

被引:50
作者
Angevin, Eric [1 ]
Isambert, Nicolas [2 ]
Trillet-Lenoir, Veronique [3 ]
You, Benoit [3 ]
Alexandre, Jerome [4 ]
Zalcman, Gerard [5 ]
Vielh, Philippe [6 ]
Farace, Francoise [6 ]
Valleix, Fanny [7 ]
Podoll, Thomas [8 ]
Kuramochi, Yu [9 ]
Miyashita, Itaru [9 ]
Hosono, Osamu [10 ]
Dang, Nam H. [11 ]
Ohnuma, Kei [12 ]
Yamada, Taketo [13 ,14 ]
Kaneko, Yutaro [15 ]
Morimoto, Chikao [12 ]
机构
[1] Univ Paris Saclay, Drug Dev Dept DITEP, Gustave Roussy, Villejuif, France
[2] Ctr Georges Francois Leclerc, Unite Phases Precoces, Dijon, France
[3] Hosp Civils Lyon, CITOHL, Inst Cancerol, Lyon, France
[4] Hop Cochin, Paris, France
[5] CHU Caen, Ctr Rech Clin, Essais Phases Precoces, Caen, France
[6] Gustave Roussy, Translat Res Lab, Villejuif, France
[7] FV Clin Subcontractor SynteractHCR SAS, Levallois Perret, France
[8] Ys Therapeut Inc, Redwood City, CA USA
[9] Kissei Pharmaceut Co Ltd, Tokyo, Japan
[10] Univ Tokyo, Inst Med Sci, IMSUT Hosp, Dept Rheumatol & Allergy, Tokyo, Japan
[11] Univ Florida, Div Hematol Oncol, Gainesville, FL USA
[12] Juntendo Univ, Grad Sch Med, Dept Therapy Dev & Innovat Immune Disorders & Can, Tokyo, Japan
[13] Keio Univ, Sch Med, Tokyo, Japan
[14] Saitama Med Univ, Saitama, Japan
[15] Ys AC Co Ltd, Tokyo, Japan
关键词
CD26; phase I; mesothelioma; immune checkpoint; MALIGNANT-PLEURAL-MESOTHELIOMA; DIPEPTIDYL-PEPTIDASE-IV; T-CELL-ACTIVATION; STEM-CELLS; OVEREXPRESSION; SURVIVAL; IMMUNITY; ANTI-1F7; MARKERS; KINASE;
D O I
10.1038/bjc.2017.62
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: YS110 is a humanised IgG1 monoclonal antibody with high affinity to the CD26 antigen. YS110 demonstrated preclinical anti-tumour effects without significant side effects. Methods: 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. Results: Thirty-three patients (22 mesothelioma) received a median of 3 (range 1-30) YS110 infusions across six dose levels (0.1-6mgkg(-1)). 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-max) increased in proportion with the dose. sCD26/DPPIV assays indicated CD26 modulation. Prolonged stable diseases were observed in 13 out of 26 evaluable patients. Conclusions: YS110 is well tolerated up to 6mg kg(-1) Q1W, which has been defined as the RP2D, with encouraging prolonged disease stabilisations observed in a number of patients with advanced/refractory mesothelioma.
引用
收藏
页码:1126 / 1134
页数:9
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