NCT05563766

A Phase II Trial to Evaluate the Effect of Itraconazole on Pathologic Complete Response Rates in Resectable Esophageal Cancer

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 78 (estimated)
• Sponsor: VA Office of Research and Development · Federal
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

Esophageal cancer, which has a low 5-year overall survival rate (\<20%) is increasing in incidence. Previous studies have shown that Hedgehog, AKT, and angiogenic signaling pathways are activated in a significant number of esophageal cancers. Itraconazole, a widely used anti-fungal medication, effectively inhibits these pathways. In this multi-site phase II trial, the investigators will evaluate the effect of itraconazole as a neoadjuvant therapy added to standard of care chemoradiation and surgery in the the treatment of locoregional esophageal and gastroesophageal junction cancers.

Detailed description

Esophageal cancer has a high incidence rate in the United States, and novel approaches to improve its treatment are being studied. Itraconazole, an antifungal agent approved by the FDA in 1992, has been shown to inhibit the Hedgehog (Hh), AKT, and VEGFR2 signaling pathways which are upregulated in esophageal cancer and promote tumor growth. This study will evaluate whether the use of itraconazole leads to increased rates of pathologic complete response (pathCR) by at least 15% compared to propensity-score matched control patients with esophageal or gastroesophageal junction (GEJ) cancer. The investigators will enroll 78 patients with esophageal or GEJ cancer who will undergo standard of care staging workup with a PET/CT and endoscopic ultrasound (EUS). If no distant metastases are found, patients will receive 2 weeks of oral itraconazole before starting standard of care neoadjuvant chemoradiation. Upon completion of chemoradiation, patients will receive oral itraconazole for 6-8 weeks. Adverse effects to itraconazole will be monitored and drug levels will be obtained during clinic visits. If standard restaging PET/CT following neoadjuvant chemoradiation does not reveal new metastases, patients will undergo esophagectomy after consultation with their physician team. Samples from normal esophageal tissue will be analyzed for presence of itraconazole and its metabolite to determine if patients were compliant in taking study drug. Residual tumor tissue will be evaluated for status of the Hh, AKT, and VEGFR2 pathways with comparisons made to pre-treatment biopsies. The final pathology report will indicate whether the patient has achieved pathCR. Because Hh, AKT, and angiogenic signaling pathways can be upregulated in response to chemoradiation, the investigators believe that administering itraconazole around chemoradiation will lead to higher pathCR rates. This in turn should be able to improve treatment outcomes in patients with esophageal and GEJ cancer. Secondary endpoints include correlating drug levels and molecular pathway status to pathCR, determining a genomic profile that predicts treatment response, and evaluating ctDNA and exosomes as additional markers of treatment response.

Conditions

• Esophageal Adenocarcinoma
• Esophageal Squamous Cell Carcinoma
• Gastroesophageal Junction Carcinoma

Interventions

Type	Name	Description
DRUG	Itraconazole	Itraconazole 300 mg po bid for two weeks prior and 6-8 weeks after completion of standard of care neoadjuvant chemoradiation

Timeline

• Start date: 2024-10-01
• Primary completion: 2029-04-30
• Completion: 2029-06-15
• First posted: 2022-10-03
• Last updated: 2025-11-05

Locations

7 sites across 1 country: United States

Regulatory

• FDA-regulated drug study