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.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Agents, Immunological/administration & dosage , Esophageal Neoplasms/drug therapy , Esophagogastric Junction/drug effects , Stomach Neoplasms/drug therapy , Aged , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacokinetics , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/pharmacokinetics , Disease Progression , Drug Dosage Calculations , Esophageal Neoplasms/pathology , Esophagogastric Junction/pathology , Female , Germany , Humans , Infusions, Intravenous , Latvia , Male , Maximum Tolerated Dose , Middle Aged , Stomach Neoplasms/pathology , Time Factors , Treatment OutcomeABSTRACT
PURPOSE: In this report, we summarise data on BRCA1 gene analysis in Latvia to characterise criteria of genetic testing for breast and ovarian cancer susceptibility. MATERIAL/METHODS: Analysis by SSCP/HD, MALDI-TOF mass spectrometry or DNA sequencing was used for mutation detection. Mutations identified were confirmed by direct DNA sequencing. RESULTS: Out of 1068 breast and 231 ovarian cancer patients from different families: 58 carried the c.5266dupC and 43 carried the c.4035delA mutations. Every 4th patient in our study did not report cancer in the family. The breast cancer was diagnosed earlier in carriers of the c.5266dupC than in carriers of the c.4035delA (p=0.003). The incidence of breast or ovarian cancer does not differ among the 2 mutation carriers in our patient group. The nature of the c.5266dupC mutation might be more deleterious. CONCLUSIONS: We recommend the screening of 4 founder BRCA1 mutations in all breast and ovarian cancer patients in Latvia at diagnosis of disease regardless of family history or age. The BRCA1 screening can be carried out efficiently using the MALDI-TOF mass spectrometry mutation detection method developed in the Biomedical Research and Study Centre (Riga, Latvia).
