Ugur Sahin1, Martin Schuler2, Heike Richly3, Stefan Bauer4, Anna Krilova5, Tobias Dechow6, Markus Jerling7, Magdalena Utsch8, Christoph Rohde8, Karl Dhaene9, Christoph Huber1, Özlem Türeci10. 1. TRON - Translational Oncology, Medical Center, Johannes Gutenberg University, Mainz, Germany. 2. West German Cancer Center, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany. 3. German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany. 4. Gemeinschaftspraxis Hematology and Oncology, Lebach, Germany. 5. Piejuras Hospital, Oncology Clinic, Liepaja, Latvia. 6. Formerly of Klinikum Rechts der Isar, Munich, Germany; Onkologie Ravensburg, Ravensburg, Germany. 7. Markus Jerling Consulting AB, Bromma, Sweden. 8. Formerly of Ganymed GmbH, Mainz, Germany. 9. MD Dhaene Pathology Lab Bvba, Destelbergen, Belgium. 10. CI3 - Cluster of Individualized Immune Intervention, Mainz, Germany. Electronic address: tureci@uni-mainz.de.
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.
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: Martin Kolev; Madhumita Das; Monica Gerber; Scott Baver; Pascal Deschatelets; Maciej M Markiewski Journal: Front Immunol Date: 2022-07-01 Impact factor: 8.786