Clinical trial NCT06732388: Itraconazole in Combination With Ablation for the Prevention of Esophageal Cancer in Patients With High-risk Barrett's Esophagus
Official title: Repurposing Itraconazole for Secondary Prevention of Metaplasia and Primary Prevention of Cancer in Patients With High-Risk Barrett's Esophagus in Combination With Ablation
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Barrett Esophagus
Clinical Stage I Esophageal Adenocarcinoma AJCC v8
Clinical Stage IIA Esophageal Adenocarcinoma AJCC v8
Esophageal Adenocarcinoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2024-12-13
Enrollment: 64
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This phase II trial tests how well itraconazole works in combination with standard of care endoscopy with ablation for the prevention of esophageal cancer in patients with high-risk Barrett's esophagus (BE). BE is a condition in which the lining of the esophagus changes. The tissue that lines the esophagus 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. It belongs to the family of drugs called antifungal agents. 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 resolution of intestinal metaplasia (CRIM) 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 arms.

ARM 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 in the absence of disease progression or unacceptable toxicity. Patients undergo 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.

ARM II: Patients receive placebo PO BID on days 1-42 of each cycle. Cycles repeat every 6 weeks for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo 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.

Eligibility criteria: 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 adequate contraception (hormonal or barrier method of birth control; abstinence) two months prior to study entry, 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
* 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

Primary outcomes:
measure: Time to complete resolution of intestinal metaplasia (CRIM) in days
timeFrame: Between day 1, cycle 1 (1 cycle = 6 weeks) and the date of endoscopy at which the participant is deemed to reach CRIM
Secondary outcomes:
measure: Time to complete eradication of dysplasia
timeFrame: Between day 1, cycle 1 (1 cycle = 6 weeks) and the date of endoscopy at which surveillance biopsies do not show dysplasia
measure: Rate of BE recurrence over follow-up
timeFrame: At 12 months after CRIM
measure: Incidence of adverse events
timeFrame: Up to 30 days after the end of intervention
measure: Correlate levels of itraconazole and its primary metabolite hydroxyitraconazole
timeFrame: After two weeks of itraconazole
measure: Biosocial impact
timeFrame: At baseline and at the end of the study
Other outcomes:
measure: Correlation of the degree of inhibition of Hh, PI3K-AKT, and VEGFR2 signaling pathways with treatment response
timeFrame: After two weeks of study drug administration
measure: Expression of stem cell markers such as LGR5/CD44/DCAMKL1
timeFrame: After two weeks of itraconazole
Locations:
city: Kansas City
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
Study officials:
affiliation: University of Michigan Rogel Cancer Center
name: Ajay Bansal
role: PRINCIPAL_INVESTIGATOR
References: