Barrett Esophagus, Clinical Stage I Esophageal Adenocarcinoma AJCC v8, Clinical Stage IIA Esophageal Adenocarcinoma AJCC v8, Esophageal Adenocarcinoma
Conditions
Brief summary
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.
Detailed description
PRIMARY OBJECTIVE: I. To evaluate if itraconazole in the peri-ablation period in participants with high-risk Barrett's esophagus (BE) can accelerate BE regression i.e., achieve complete eradication of intestinal metaplasia (CEIM) faster than the control group. SECONDARY OBJECTIVES: I. To measure the time to event of complete eradication of dysplasia (CED). II. To measure the rate of BE recurrence during routine follow-up. III. To determine the safety and tolerability of itraconazole in participants with high-risk BE. IV. To correlate levels of itraconazole and its primary metabolite hydroxyitraconazole in plasma and esophageal tissues with treatment response. V. To compare biosocial impact on the participants in the itraconazole and control arms. EXPLANATORY OBJECTIVE: I. To correlate the degree of inhibition of Hedgehog (Hh), PI3K-AKT, and VEGFR2 signaling pathways with treatment response. EXPLORATORY OBJECTIVES: I. To determine whether expression (baseline and magnitude of change) of stem cell markers such as LGR5/CD44/DCAMKL1 can predict treatment response. II. To bank blood samples and tissue biopsies for future analyses to understand the determinants of response. OUTLINE: Patients are randomized to 1 of 2 groups. GROUP I: Patients receive itraconazole orally (PO) twice daily (BID) on days 1-42 of each cycle. Cycles repeat every 6 weeks for up to 2 cycles as long as there is an absence of disease progression or unacceptable toxicity. Patients undergo usual standard of care endoscopy and radiofrequency ablation on study. Patients also undergo blood sample collection throughout the study as well as tissue biopsy on study. GROUP II: Patients receive placebo PO BID on days 1-42 of each cycle. Cycles repeat every 6 weeks for up to 2 cycles as long as there is an absence of disease progression or unacceptable toxicity. Patients undergo usual standard of care endoscopy and radiofrequency ablation on study. Patients also undergo blood sample collection throughout the study as well as tissue biopsy on study. After completion of study treatment, patients are followed up at 12 months.
Interventions
PROCEDUREBiopsy Procedure
Undergo tissue biopsy
PROCEDUREBiospecimen Collection
Undergo blood sample collection
PROCEDUREEndoscopic Procedure
Undergo endoscopy
DRUGItraconazole
Given PO
DRUGPlacebo Administration
Given PO
OTHERQuestionnaire Administration
Ancillary studies
PROCEDURERadiofrequency Ablation
Undergo radiofrequency ablation
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
The participants as well as the study team will be blinded to the study drug assignment. The study endoscopist will be blinded to the treatment group to avoid bias. Will ensure that the laboratory personnel running the assays are blinded to the allocation.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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 * Absolute neutrophil count ≥ 1,000/microliter * Platelets ≥ 100,000/microliter * Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) * Note: Higher total bilirubin levels (≤ 3 mg/dL) can be allowed if due to known benign liver condition, i.e. Gilbert's * Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase \[SGPT\]) ≤ 1.5 × institutional upper limit of normal * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial * For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated * Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load * Participants on chronic suppressive antiviral therapy for herpes simplex virus (HSV) are eligible * There are no controlled data on the effects of itraconazole on the developing human fetus at the recommended therapeutic dose. For this reason and because azoles are known to be teratogenic, women of child-bearing potential must agree to use one or more methods of highly effective contraception that do not contain estrogen (e.g. progestin only oral contraceptive, non-hormonal intrauterine device, bilateral tubal ligation) two months prior to study entry, for the duration of study participation and two months after completing the study drug. Women should not donate eggs or participate in in vitro fertilization for the duration of study participation, and two months after completing the study drug. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately. Male subjects should avoid donating sperm, and if engaged in intercourse with women of child-bearing potential use a method of highly effective contraception. * Activities of Reproductive Potential: In addition to heterosexual intercourse, activities that could lead to pregnancy (e.g. sperm or egg donation, participation in in vitro fertilization) should be considered when evaluating the reproductive potential of clinical trial subjects. * Females of Reproductive Potential: A non-post-menopausal female who has not had a bilateral oophorectomy or medically documented ovarian failure. A female who has had a tubal ligation sterilization, or hysterectomy would not be considered to be of reproductive potential unless participating in activities of reproductive potential other than heterosexual intercourse (e.g. egg donation, participation in in vitro fertilization). * Menopause: * Twelve (12) months of spontaneous amenorrhea or; * Spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels \> 40 mIU/mL or; * Subject is post-bilateral oophorectomy with or without hysterectomy * Ability to understand and the willingness to sign a written informed consent document
Exclusion criteria
* 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 * Uncontrolled intercurrent illness., or psychiatric illness/social situations that would limit compliance with study requirements * Pregnant women are excluded from this study because itraconazole is a class C agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with itraconazole, breastfeeding should be discontinued if the mother is treated with itraconazole * Critical drug interactions (grades D or higher) with other medications metabolized by cytochrome P450(CYP)3A4 (if the medication cannot be discontinued or switched or dose modified); these decisions will be made on a case-by-case basis by the site investigators in consultation with the treating provider. Drug interactions can be assessed using one of the available on-line resources, for instance, UpToDate or Clinical Formulary and/or in collaboration with a clinical pharmacist. * Note: If there are potential drug interactions that do not exclude the participant from the study, a brief research note summarizing the decision-making process about potential drug interactions and their management will be required before the participants are enrolled in the trial * History of eosinophilic esophagitis * History of strictures not allowing passage of the radiofrequency ablation (RFA) assembly * Participants must not have evidence of active/recurrent invasive cancer of a non-esophageal organ * Participants with EAC greater than stage T1a * Persistent (\> 24 hour \[h\]) systolic blood pressure (BP) greater than or equal to 160 mmHg (to avoid reaching hypertensive crisis defined as systolic BP \> 180 mmHg) * Patients taking eliglustat. Co-administration of itraconazole and eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to complete eradication of intestinal metaplasia (CEIM) in days | Between day 1, cycle 1 (1 cycle = 6 weeks) and the date of endoscopy at which the participant is deemed to reach CEIM | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to complete eradication of dysplasia | Between day 1, cycle 1 (1 cycle = 6 weeks) and the date of endoscopy at which surveillance biopsies do not show 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 | At 12 months after CEIM | 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 | Up to 30 days after the end of intervention | 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 | After two weeks of itraconazole | 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. |
| Biosocial impact | At baseline and at the end of the study | Will be assessed by questionnaires to collect information about the biosocial endpoints. These will include cancer-specific distress questionnaire, Gastrointestinal Symptom Rating Scale, Health-Related Quality of life short form 12 version 2, and Patient-Reported Outcomes Measurement Information System anxiety and depression scores as previously used at the beginning and at the end of the study. The summary measures such as mean or median of these distress scores will be compared between arms using t-test (or Wilcoxon rank test in case of non normality). Linear regression models will be used for studying the differences in the average distress scores between arms adjusted for age, sex and prior history of anxiety or depression. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAjay Bansal, MD
University of Kansas Medical Center
Outcome results
None listed