Evaluating the Effect of Itraconazole on Pathologic Complete Response Rates in Esophageal Cancer

  • STATUS
    Recruiting
  • End date
    Sep 29, 2026
  • participants needed
    78
  • sponsor
    Dallas VA Medical Center
Updated on 12 February 2022
cancer
carcinoma
AKT
chemoradiotherapy
esophageal cancer
adjuvant therapy

Summary

Esophageal cancer, which has a low 5-year overall survival rate for all stages (<20%) , is increasing in incidence. Previous studies have shown that the Hedgehog (Hh) and AKT signaling pathways are activated in a significant proportion of esophageal cancers. Itraconazole, a widely used anti-fungal medication, has been shown to inhibit various pathways involved in esophageal cancer tumorigenesis including Hh and AKT. In this phase II clinical trial, the investigators aim to evaluate the effect of itraconazole as a neoadjuvant therapy following standard of care chemoradiation in the treatment of locoregional esophageal and gastroesophageal junction carcinomas.

Description

Esophageal cancer has a high incidence rate in the United States, and novel approaches to its treatment are being studied. Itraconazole, an antifungal agent, has been shown to inhibit the Hedgehog (Hh) and AKT signaling pathways, which are upregulated in esophageal cancer and promote tumor cell growth. This study will evaluate whether the use of itraconazole leads to increased rates of pathological complete response (pathCR) by at least 15% from the historical pathCR rate of 25% in patients with esophageal cancer or gastroesophageal junction (GEJ) adenocarcinoma. The investigators will enroll approximately 78 patients with esophageal cancer or GEJ adenocarcinoma who will then undergo standard of care staging work-up with a PET/CT and endoscopic ultrasound (EUS). In a subset of patients, biopsies will be obtained to assess the status of the Hh and AKT signaling pathways by PCR, Western blot, and immunohistochemistry in the primary tumor before treatment. If no distant metastases are found, all patients will undergo 5-6 weeks of standard of care neoadjuvant chemoradiation. Following this, all patients will be given itraconazole 300 mg twice daily for 6-8 weeks. Adverse effects to itraconazole will be monitored in oncology clinic. If standard restaging PET/CT following neoadjuvant chemoradiation does not reveal new metastases, the patient will undergo an esophagectomy. Samples from normal esophageal tissue will be analyzed for presence of itraconazole and its metabolites to determine if the patients were taking the study drug. Tumor tissue will be evaluated for status of Hh pathway activation, AKT and VEGFR2 phosphorylation, Ki67 immunostaining, and other molecular pathways with comparisons made to pre-treatment biopsies if available. The final pathology report will indicate whether the patient has achieved pathCR. Because the Hh signaling pathway is a resistance pathway that can be upregulated in response to chemoradiation, the investigators believe that administering itraconazole following neoadjuvant chemoradiation will lead to a higher pathCR rate. This in turn should be able to improve treatment outcomes in patients with esophageal cancer and GEJ adenocarcinoma.

Details
Condition Esophagus Adenocarcinoma, Esophagus Squamous Cell Carcinoma, Gastroesophageal Junction Adenocarcinoma
Treatment Itraconazole
Clinical Study IdentifierNCT04018872
SponsorDallas VA Medical Center
Last Modified on12 February 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Patients diagnosed with localized (locoregional) esophageal cancer
Patients diagnosed with localized (locoregional) gastroesophageal junction cancer

Exclusion Criteria

Patients unwilling or unable to provide informed consent
Patients with QTc>450ms
Patients with a history of symptomatic congestive heart failure
Patients with LFT's>3xULN
Patients who are pregnant
Patients with a known allergy to itraconazole
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