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

Our plain-English summary of First-in-human phase 1 of YS110, a monoclonal antibody directed against CD26 in advanced CD26-expressing cancers, by E. Angevin, N. Isambert, V. Trillet-Lenoir, et al (British Journal of Cancer, 2017).

The study

• Authors: E. Angevin, N. Isambert, V. Trillet-Lenoir, B. You, J. Alexandre, G. Zalcman, P. Vielh, F. Farace, F. Valleix, T. Podoll, Y. Kuramochi, I. Miyashita, O. Hosono, N.H. Dang, K. Ohnuma, T. Yamada, Y. Kaneko, C. Morimoto
• Journal: British Journal of Cancer
• Published: 2017;116(9):1126-1134
• Cited by: 51 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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 (0.1-6 mg kg-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 Cmax) 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 6 mg 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.

In plain English

This was a first-in-human phase 1 trial of YS110, an antibody drug aimed at CD26, a molecule found on some tumours. Of 136 patients screened, 56 had CD26-positive tumours. Thirty-four were enrolled at five sites in France and 33 were evaluable. Most had mesothelioma, all of the epithelioid type; the rest had renal cell carcinoma or, in one case, urothelial carcinoma. Doses rose from 0.1 to 6 mg per kg, given first every two weeks and later weekly. The highest dose was reached without finding a maximum tolerated dose. Two patients had grade 3 infusion reactions, after which steroid premedication was added. Side effects counted as possibly, probably or definitely related to the drug, or of unknown relationship to it, were reported by 30 patients (90.9%), most often low-grade asthenia (30.3%) and hypersensitivity (27.3%). No patient had an objective tumour response. Disease was stable in 13 of 26 evaluable patients, and seven patients (five with mesothelioma) went 184 to 399 days without progression. The authors concluded the drug was generally well tolerated up to 6 mg per kg weekly, their recommended phase 2 dose.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: First-in-human phase 1 dose-escalation trial (3+3 design) of a single drug, YS110
• Who was studied: 34 patients with advanced or refractory CD26-positive solid tumours were enrolled at 5 sites in France; 33 were evaluable (19 males, 14 females). Mesothelioma patients all had epithelioid histology. The other patients had renal cell carcinoma and one had urothelial carcinoma. Study dates are not given.
• Exposure: Intravenous YS110, an anti-CD26 monoclonal antibody, at 0.1, 0.4, 1 and 2 mg per kg every two weeks (three infusions per cycle), then at 2, 4 and 6 mg per kg weekly (five infusions per cycle). Asbestos exposure is not studied.
• Main results:
  • 136 patients were screened for CD26 expression; 56 (41%) were CD26-positive
  • Two dose-limiting toxicities occurred, both grade 3 infusion reactions; the maximum tolerated dose was not reached at the highest dose tested (6 mg per kg)
  • The study defined an adverse drug reaction as an adverse event documented as possibly, probably or definitely related to the study drug, or with unknown relationship to it
  • 113 adverse drug reactions possibly related to YS110 were reported by 30 (90.9%) of 33 patients
  • Adverse drug reactions among the 33 patients included low-grade asthenia (30.3%), hypersensitivity (27.3%), nausea (15.2%), flushing (15.2%), chills (12.1%) and pyrexia (12.1%)
  • Eight patients (24.2%) stopped YS110 because of adverse events. All serious adverse events other than the two dose-limiting toxicities, including six deaths, were judged by the investigator to be unrelated to YS110.
  • No objective tumour response was seen. Stable disease was the best response in 13 of 26 evaluable patients after the first cycle.
  • Overall median progression-free survival was 43 days. Seven of 26 patients (five with mesothelioma, two with renal cell carcinoma) had progression-free survival of 184 to 399 days.
  • Higher YS110 doses were associated with lower serum soluble CD26 levels, particularly at 2, 4 and 6 mg per kg (about an 80% decrease)
  • The authors considered it probable that hyperglycaemia in the higher-dose groups was caused by the corticosteroid premedication, not by YS110
• The authors' conclusion: The authors concluded that YS110 was generally well tolerated up to 6 mg per kg weekly, which they defined as the recommended phase 2 dose. They reported encouraging disease stabilisation in a number of patients and suggested that further development, such as combination therapy, is warranted.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Monoclonal Antibody, Mesothelioma.

Related studies

• Phase I study of YS110, a recombinant humanized monoclonal antibody to CD26, in Japanese patients with advanced malignant pleural mesothelioma — M. Takeda, Y. Ohe, et al. (2019)
• Phase I study of amatuximab, a novel monoclonal antibody to mesothelin, in Japanese patients with advanced solid tumors — Y. Fujisaka, T. Kurata, et al. (2015)
• Establishment of monoclonal anti-human CD26 antibodies suitable for immunostaining of formalin-fixed tissue — R. Hatano, T. Yamada, et al. (2014)
• Establishment of Mouse Monoclonal Antibody LpMab-13 Against Human Podoplanin — S. Ogasawara, M.K. Kaneko, et al. (2016)
• Nuclear localization of CD26 induced by a humanized monoclonal antibody inhibits tumor cell growth by modulating of POLR2A transcription — K. Yamada, M. Hayashi, et al. (2013)
• First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody-Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors — R. Hassan, G.R. Blumenschein, et al. (2020)

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