Journal
BRITISH JOURNAL OF CANCER
Volume 116, Issue 9, Pages 1126-1134Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2017.62
Keywords
CD26; phase I; mesothelioma; immune checkpoint
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Funding
- Y'AC Co., Ltd, Tokyo, Japan
- Kissei Pharmaceutical Co., Ltd, Tokyo, Japan
- Japan Agency for Medical Research and Development (AMED)
- Grants-in-Aid for Scientific Research [15H04879, 16H05345, 15K15324, 16H04714] Funding Source: KAKEN
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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.
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