A phase I dose-escalation study of IMAB362 (Zolbetuximab) in patients with advanced gastric and gastro-oesophageal junction cancer.

Abstract

INTRODUCTION:

IMAB362 (Zolbetuximab) is a chimeric monoclonal antibody that binds to Claudin-18.2, a target antigen specific to cancer cells. In vitro, IMAB362 mediates cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity; thus, IMAB362 may serve as a potent, targeted immunotherapeutic agent.

METHODS:

This first-in-human phase I study enroled adult patients (N = 15) with advanced gastric or gastro-oesophageal junction cancer into five sequential single dose-escalation cohorts (33, 100, 300, 600, and 1000 mg/m2) following a 3 + 3 design. Safety/tolerability, including determination of maximum tolerated dose and recommended phase II dose, were the primary objectives; secondary objectives included assessment of the IMAB362 pharmacokinetic profile, immunogenicity, and antitumour activity (assessed by Response Evaluation Criteria in Solid Tumors v1.0).

RESULTS:

IMAB362 was generally well tolerated at all doses, with gastrointestinal toxicities being the most commonly observed treatment-related adverse events. As dose-limiting toxicity was not observed within 4 weeks of treatment, a maximum tolerated dose was not established. The pharmacokinetic profile of IMAB362 appeared to be proportional across the dose range; and mean half-life ranged from 13 to 24 d. While most patients showed progressive disease at weeks 4-5 after a single intravenous IMAB362 infusion, one patient in the 600 mg/m2 dose group achieved and maintained stable disease for approximately 2 months postinfusion.

CONCLUSIONS:

Findings from this study demonstrate that IMAB362 is generally well tolerated and support further evaluation in patients with gastric/gastro-oesophageal junction cancer.

CLINICAL TRIAL REGISTRY:

ClinicalTrials.gov, Identifier NCT00909025.

• Authors: Ugur Sahin, Martin Schuler, Heike Richly, Stefan Bauer, Anna Krilova, Tobias Dechow, Markus Jerling, Magdalena Utsch, Christoph Rohde, Karl Dhaene, Christoph Huber, Özlem Türeci
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 100 Pg. 17-26 (09 2018) ISSN: 1879-0852 [Electronic] England
• PMID: 29936063 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents, Immunological
• zolbetuximab

Topics

• Aged
• Antibodies, Monoclonal (administration & dosage, adverse effects, pharmacokinetics)
• Antineoplastic Agents, Immunological (administration & dosage, adverse effects, pharmacokinetics)
• Disease Progression
• Drug Dosage Calculations
• Esophageal Neoplasms (drug therapy, pathology)
• Esophagogastric Junction (drug effects, pathology)
• Female
• Germany
• Humans
• Infusions, Intravenous
• Latvia
• Male
• Maximum Tolerated Dose
• Middle Aged
• Stomach Neoplasms (drug therapy, pathology)
• Time Factors
• Treatment Outcome