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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Esophageal Adenocarcinoma, Esophageal Squamous Cell Carcinoma, Gastroesophageal Junction Carcinoma

Intervention / Treatment
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* Drug: Itraconazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capable of giving informed consent Pathologic diagnosis of esophageal cancer (ESCC or EAC) or GEJ cancer deemed resectable by a surgeon with a plan to undergo neoadjuvant chemoradiation and curative intent esophagectomy World Health Organization (WHO)/ECOG performance status (PS) of 0-2 at enrollment Adequate renal and liver function as judged by the treating physician Exclusion Criteria: Inability to provide Informed Consent NYHA class III or IV CHF LFT>3X upper limit of normal Drug allergy to itraconazole Positive pregnancy test Those with QTc>450 ms will have QTc monitored during therapy by serial EKG to ensure QTc does not lengthen to what the treating clinician considers significant

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single arm, patients will receive itraconazole 300 mg po bid for two weeks prior and 6-8 weeks after standard of care neoadjuvant chemoradiation.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Itraconazole<br>Itraconazole 300 mg po bid for two weeks prior and 6-8 weeks after completion of standard of care neoadjuvant chemoradiation | Drug: Itraconazole<br>* Itraconazole 300 mg po bid for two weeks prior and 6-8 weeks after completion of standard of care neoadjuvant chemoradiation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of pathological complete response with itraconazole | Historically, the pathCR rate at time of esophagectomy is 25%. The investigators have powered our study to detect a 15% or more improvement in pathCR rate following treatment with itraconazole. By inhibiting pathways that mediate chemoradiation resistance, the investigators anticipate an improved pathCR rate. | 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of Hedgehog, AKT, and angiogenesis pathway status before and after intervention | After completion of pathologic staging of any residual tumor at esophagectomy, FFPE sections will be analyzed for expression of SHH, GLI, HER2, phospho-S6, and CD34 by IHC or ISH and compared to untreated biopsies. | 20 weeks | 
| Correlation of peripheral blood and esophageal tissue levels of itraconazole and hydroxyitraconazole with pathologic response | Peripheral blood will be obtained during a standard of care clinic visit and squamous esophageal tissue collected at esophagectomy. These levels will be correlated with pathologic response. | 20 weeks | 
| Develop a predictive genomic profile of treatment response | Whole exome sequencing will be obtained on pre-treatment tumors from all enrolled patients. VA Boston HCS will use multiple algorithms to develop a genomic profile that predicts treatment response. | 20 weeks | 
| Determine the utility of ctDNA and exosome characterization as a prognostic marker | CtDNA will be obtained at 4 timepoints and exosomes will be collected at 3 timepoints during treatment. Changes in ctDNA quantitation and exosome characteristics will be correlated with pathologic treatment response. | 20 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Itraconazole, Neoadjuvant