Phase I study of YS110, a recombinant humanized monoclonal antibody to CD26, in Japanese patients with advanced malignant pleural mesothelioma

Our plain-English summary of Phase I study of YS110, a recombinant humanized monoclonal antibody to CD26, in Japanese patients with advanced malignant pleural mesothelioma, by M. Takeda, Y. Ohe, H. Horinouchi, et al (Lung Cancer, 2019).

The study

• Authors: M. Takeda, Y. Ohe, H. Horinouchi, T. Hida, J. Shimizu, T. Seto, K. Nosaki, T. Kishimoto, I. Miyashita, M. Yamada, Y. Kaneko, C. Morimoto, K. Nakagawa
• Journal: Lung Cancer
• Published: 2019;137:64-70
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objectives: CD26 is a transmembrane glycoprotein with dipeptidyl peptidase IV activity that is overexpressed in malignant pleural mesothelioma (MPM). We performed a phase I study to determine the maximum tolerated dose, pharmacokinetics, and antitumor activity of YS110, a monoclonal antibody to CD26, in Japanese patients with MPM intolerant of or refractory to prior standard therapies.

Material And Methods: The study was designed as an open-label, 3 + 3 dose-escalation, phase I trial. Patients were sequentially assigned to three dosing cohorts (2, 4, or 6 mg/kg). Each 6-week treatment cycle consisted of YS110 administration weekly for 5 weeks followed by a 1-week rest period. Treatment was continued until disease progression, death, or intolerable toxicity. Corticosteroid, antihistamine, and acetaminophen administration before each infusion was adopted to limit infusion-related reactions (IRRs).

Results: Nine Japanese patients (seven men and two women, mean age of 62.2 years), three in each dosing cohort, were enrolled in the study. No patient developed a dose-limiting toxicity. Adverse events of grade 3 or 4 developed in seven patients, with the most common such event being a decreased lymphocyte count. Two patients had mild or moderate IRRs. The serum concentration of YS110 increased in a dose-dependent manner. Among seven patients evaluable for tumor response, four showed stable disease and one achieved a partial response.

Conclusions: YS110 showed promising antitumor efficacy and was generally well tolerated in Japanese patients with advanced MPM at doses of up to 6 mg/kg. YS110 will be tested at 6 mg/kg in a subsequent phase II study.

Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

In plain English

This was a small, open-label phase I trial in nine Japanese patients with advanced malignant pleural mesothelioma. Earlier standard treatment had failed or could not be tolerated. The drug, YS110, is an antibody targeting a protein called CD26. The study did not look at asbestos exposure. Three patients were assigned to each dose (2, 4 or 6 mg/kg). The plan was weekly infusions for five weeks per six-week cycle, with premedication to limit infusion reactions. One patient each at 2 and 6 mg/kg stopped during the first cycle. No patient had a dose-limiting toxicity, and the maximum tolerated dose was taken as 6 mg/kg. The article reports grade 3 adverse events in seven patients and a grade 4 lymphocyte fall in one. Investigators attributed the lymphocyte falls to the steroid premedication, not YS110. One patient stopped treatment because of nephrotic syndrome. Of seven patients with assessable tumors, one had a partial response and four had stable disease. Median overall survival was 9.5 months (95% CI, 2.2 months to not evaluable). The authors concluded that YS110 was generally well tolerated up to 6 mg/kg, the dose recommended for phase II.

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: Open-label, standard 3 + 3 dose-escalation phase I trial (the phase I part of a phase I-II study) of a drug treatment
• Who was studied: Nine Japanese patients (seven men, two women; mean age 62.2 years) with advanced malignant pleural mesothelioma that was intolerant of or refractory to existing drugs, three in each dose cohort, treated at four participating hospitals in Japan; study dates not stated in the text
• Exposure: Not an asbestos exposure study. The exposure was the drug YS110 (a humanized monoclonal antibody to CD26) at 2, 4 or 6 mg/kg, planned as weekly infusions for 5 weeks followed by 1 week of rest per 6-week cycle
• Main results:
  • Not all patients received the full first cycle: one patient in the 2 mg/kg cohort and one in the 6 mg/kg cohort discontinued treatment during cycle 1
  • No dose-limiting toxicities were seen in any cohort, so the maximum tolerated dose was considered to be 6 mg/kg
  • Grade 3 adverse events developed in seven patients, and a grade 4 lymphocyte count decrease occurred in one patient
  • Investigators considered all cases of lymphocyte count decrease to be unrelated to YS110 and related to steroid; all patients recovered
  • One patient in the 2 mg/kg cohort stopped treatment after hospitalization with grade 3 nephrotic syndrome; this was the only treatment discontinuation caused by an adverse event
  • Three infusion-related reactions (one grade 2, two grade 1) occurred in two patients
  • Exposure to YS110 in the blood increased with repeated doses at each dose level
  • Antibodies to YS110 with neutralizing activity were detected after treatment in two patients
  • Of the seven patients evaluable for tumor response, the best response was a partial response in one patient and stable disease in four patients
  • In a post hoc analysis, 55.6% (95% CI, 21.2%–86.3%) of patients had stable disease or a partial response after the first treatment cycle
  • Median progression-free survival was 3 months (95% CI, 1.4 months to not evaluable)
  • Median overall survival was 9.5 months (95% CI, 2.2 months to not evaluable); 78% were alive at 3 months
  • Mean soluble CD26 concentration in the blood fell from 734.6 μg/L at baseline to 333.4 μg/L after the first dose
• The authors' conclusion: The authors concluded that YS110 was generally well tolerated at doses up to 6 mg/kg in Japanese patients with advanced malignant pleural mesothelioma, and that this is the recommended dose for the phase II part of the study
• Limitations the authors state:
  • The small number of patients in each dose cohort meant that racial differences in how the body handles YS110 could not be examined
  • The effect of neutralizing antibodies on drug levels was not evaluated, because serial drug-level data were not collected after cycle 1
  • CD26 expression in tumor tissue was not measured, so its relation to tumor response could not be examined

Topics

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

Medical terms in this study, explained in our Lexicon: Monoclonal Antibody, Pleural Mesothelioma, Glycoprotein, Disease Progression.

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