This phase II trial tests how well itraconazole works in combination with the usual standard of care endoscopy with ablation for the prevention of esophageal cancer in patients who have high-risk Barrett's esophagus (BE). BE is a condition in which the lining of the esophagus changes and becomes more like the tissue that lines the intestine. People with Barrett's esophagus have a higher risk of developing esophageal cancer. Itraconazole is a drug used to prevent or treat fungal infections. Ablation refers to the removal of abnormal tissue using heat. Endoscopy is a procedure for looking at the esophagus using a long, flexible tube called an endoscope, which has a video camera at the end. Radiofrequency ablation is a type of heat therapy that uses radiofrequency energy (similar to microwave heat) to destroy the abnormal tissue in the esophagus. Giving itraconazole in combination with standard of care endoscopy with ablation may improve the effects of ablation and prevent esophageal cancer in patients with high-risk Barrett's esophagus.
Participants with history of prior esophagogastroduodenoscopy (EGD) with an established diagnosis of BE ≥ 2 cm with either low-grade dysplasia (LGD) or high-grade dysplasia (HGD) or T1a esophageal adenocarcinoma (EAC), naïve to treatment, and being considered for ablation.
Note: An eligible diagnosis from an EGD outside of the enrollment sites is allowed for inclusion as long as the biopsies have been reviewed by two pathologists. The two pathologists could include a pathologist from the referring site and an institutional pathologist at the local enrolling site, two pathologists from the referring site, or two pathologists from the local enrolling site. The diagnosis between two pathologists has to be concordant regarding the presence of dysplasia or cancer. Discrepant diagnoses will be resolved by a third pathologist, if needed
Participants older than 18 years will be enrolled. Because the incidence of BE and related cancer is very low in participants < 18 years of age, children are excluded from this study
Clinically eligible for EGD and endoscopic treatment of BE
Current New York Heart Association (NYHA) class III or IV congestive heart failure
Prolonged corrected QT (QTc) (> 450 ms for men and > 470 ms for women)
Participants may not be receiving any other investigational agents
History of allergic reactions attributed to compounds of similar chemical or biologic composition to itraconazole
Parallel
Biopsy Procedure
Procedure/SurgeryUndergo tissue biopsy
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Endoscopic Procedure
Procedure/SurgeryUndergo endoscopy
Itraconazole
DrugGiven PO
Placebo Administration
DrugGiven PO
Questionnaire Administration
Other interventionAncillary studies
Radiofrequency Ablation
Procedure/SurgeryUndergo radiofrequency ablation
Time to complete eradication of intestinal metaplasia (CEIM) in days
CEIM will be defined based on the absence of visible Barrett's esophagus (BE) and invisible BE (i.e., no intestinal metaplasia \[IM\] in biopsies of the gastroesophageal junction and the cardia). Will be reported descriptively. Will compare the unadjusted hazard rates between the itraconazole and control groups using log rank test.
Time to complete eradication of dysplasia
Will be assessed by surveillance biopsies at the time of the endoscopy that documents CEIM and the biopsies at the time of first surveillance endoscopy will be evaluated for dysplasia.
Rate of BE recurrence over follow-up
Will be assessed between the study treatment group and the control group. BE recurrence will be defined as histologic presence of IM (with or without dysplasia) in biopsies from the tubular esophagus or in biopsies at the gastroesophageal junction. The results from the standard of care endoscopy closest to the 12-month time point after CEIM will be used to collect information for this endpoint.
Incidence of adverse events
Will be assessed by National Cancer Institutes Common Terminology Criteria for Adverse Events version 5.0 criteria to document adverse events and measure specific laboratory parameters to monitor for the safety and tolerability of itraconazole and assessed by descriptive statistics.
Correlate levels of itraconazole and its primary metabolite hydroxyitraconazole
Will be assessed in plasma and esophageal tissues with treatment response. Will measure these metabolites after two weeks of itraconazole therapy by obtaining biopsies of the esophagus. These measurements will be correlated with biomarker and clinical response to understand how tissue levels of the drug change the molecular and primary endpoints. Will also measure the blood levels to test the feasibility of blood levels for prediction of clinical response in the future.
Correlation of the degree of inhibition of Hh, PI3K-AKT, and VEGFR2 signaling pathways with treatment response
Measures will be assessed in biopsies of the gastroesophageal junction as well as in biopsy of BE after two weeks of study drug administration by histological techniques.
Expression of cancer stem cell markers such as LGR5/CD44/DCAMKL1
Measures will be assessed in biopsies of the gastroesophageal junction as well as biopsies of BE after two weeks of study drug administration by histological techniques.
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