Clinical trial NCT04018872: Evaluating the Effect of Itraconazole on Pathologic Complete Response Rates in Esophageal Cancer
Official title: A Phase II Trial Evaluating the Effectiveness of Itraconazole in Improving Pathologic Complete Response Rates in Patients With Esophageal Cancer Through Inhibition of the Hedgehog and AKT Signaling Pathways
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Esophagus Adenocarcinoma
Esophagus Squamous Cell Carcinoma
Gastroesophageal Junction Adenocarcinoma
Keywords: itraconazole
esophageal neoplasms
esophagus
esophagogastric junction
adenocarcinoma
squamous cell carcinoma
Lead sponsor: Dallas VA Medical Center
Sponsor class: FED
First posted: 2019-07-15
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of pathological complete response with itraconazole
timeFrame: 3-4 months
Secondary outcomes:
measure: Comparison of hedgehog biomarkers before and after intervention
timeFrame: 3-4 months
measure: Comparison of phosphorylated VEGFR2 and AKT before and after intervention
timeFrame: 3-4 months
measure: Levels of itraconazole and metabolites in esophageal tissue
timeFrame: 1 month.
Other outcomes:
Locations:
city: Dallas
country: United States
facility: Dallas VA Medical Center
state: Texas
Study officials:
affiliation: North Texas Veterans Healthcare System
name: David Wang, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kim DJ, Kim J, Spaunhurst K, Montoya J, Khodosh R, Chandra K, Fu T, Gilliam A, Molgo M, Beachy PA, Tang JY. Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. J Clin Oncol. 2014 Mar 10;32(8):745-51. doi: 10.1200/JCO.2013.49.9525. Epub 2014 Feb 3.
citation: Antonarakis ES, Heath EI, Smith DC, Rathkopf D, Blackford AL, Danila DC, King S, Frost A, Ajiboye AS, Zhao M, Mendonca J, Kachhap SK, Rudek MA, Carducci MA. Repurposing itraconazole as a treatment for advanced prostate cancer: a noncomparative randomized phase II trial in men with metastatic castration-resistant prostate cancer. Oncologist. 2013;18(2):163-73. doi: 10.1634/theoncologist.2012-314. Epub 2013 Jan 22.
citation: Nacev BA, Grassi P, Dell A, Haslam SM, Liu JO. The antifungal drug itraconazole inhibits vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, trafficking, and signaling in endothelial cells. J Biol Chem. 2011 Dec 23;286(51):44045-44056. doi: 10.1074/jbc.M111.278754. Epub 2011 Oct 24.
citation: Kim J, Tang JY, Gong R, Kim J, Lee JJ, Clemons KV, Chong CR, Chang KS, Fereshteh M, Gardner D, Reya T, Liu JO, Epstein EH, Stevens DA, Beachy PA. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell. 2010 Apr 13;17(4):388-99. doi: 10.1016/j.ccr.2010.02.027.
citation: Chen MB, Liu YY, Xing ZY, Zhang ZQ, Jiang Q, Lu PH, Cao C. Itraconazole-Induced Inhibition on Human Esophageal Cancer Cell Growth Requires AMPK Activation. Mol Cancer Ther. 2018 Jun;17(6):1229-1239. doi: 10.1158/1535-7163.MCT-17-1094. Epub 2018 Mar 28.