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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04018872
Recruitment Status : Recruiting
First Posted : July 15, 2019
Last Update Posted : July 18, 2019
Information provided by (Responsible Party):
David Wang, Dallas VA Medical Center

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.

Condition or disease Intervention/treatment Phase
Esophagus Adenocarcinoma Esophagus Squamous Cell Carcinoma Gastroesophageal Junction Adenocarcinoma Drug: Itraconazole Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 78 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : June 24, 2019
Estimated Primary Completion Date : June 24, 2022
Estimated Study Completion Date : September 29, 2022

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Itraconazole
Itraconazole capsule 300mg twice daily for 6-8 weeks following chemoradation.
Drug: Itraconazole
Oral administration of itraconazole twice daily from completion of neoadjuvant chemoradiation until esophagectomy.

Primary Outcome Measures :
  1. Percentage of pathological complete response with itraconazole [ Time Frame: 3-4 months ]
    Generally for esophageal cancer the pathological complete response rate at time of esophagectomy is 25%, and we have designed our study with the projected number of patients assuming we observe an improvement of 15% or more in this rate following treatment with itraconazole. This is the study's primary endpoint. By inhibiting the Hh signaling pathway with the use of itraconazole, we anticipate improved pathological complete response rates.

Secondary Outcome Measures :
  1. Comparison of hedgehog biomarkers before and after intervention [ Time Frame: 3-4 months ]
    As part of clinical staging, patients will undergo endoscopic ultrasound (EUS) following a PET/CT that does not show metastases. During EUS, some patients will undergo eight research biopsies obtained with large forceps for research purposes at the level of the visualized esophageal mass or abnormality (3 for RNA isolation, 3 for protein isolation, and 2 for formalin fixation). Three research biopsies for RNA isolation will also be obtained from normal appearing esophagus, at least 5 cm away from any mass lesions. The research biopsies will be submitted to qPCR analysis for mRNA expression levels of SHH, IHH, PTCH, GLI1, GLI2, and GLI3 (Hedgehog pathway components). Comparisons will be made between mass biopsies and normal esophageal tissues. Following esophagectomy, tissues will be analyzed for the aforementioned hedgehog pathway markers to determine response to therapy.

  2. Comparison of phosphorylated VEGFR2 and AKT before and after intervention [ Time Frame: 3-4 months ]
    Tissue obtained prior to initiation of chemoradiation will be analyzed with Western blot to quantify presence of VEGFR2 and AKT. These markers will again be analyzed following esophagectomy to determine response to therapy.

  3. Levels of itraconazole and metabolites in esophageal tissue [ Time Frame: 1 month. ]
    The concentration of itraconazole and hydroxy-itraconazole in normal esophageal tissue will be measured following esophagectomy to ensure that the drug has been taken consistently.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04018872

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Contact: David Wang, MD, PhD 214-857-0737
Contact: Thai Pham, MD 214-857-1800

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United States, Texas
Dallas VA Medical Center Recruiting
Dallas, Texas, United States, 75216
Contact: Jessica Vallejo, BSA         
Contact    214-857-4237   
Sponsors and Collaborators
Dallas VA Medical Center
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Principal Investigator: David Wang, MD, PhD North Texas Veterans Healthcare System


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Responsible Party: David Wang, Staff Physician, Dallas VA Medical Center Identifier: NCT04018872     History of Changes
Other Study ID Numbers: 19-017
First Posted: July 15, 2019    Key Record Dates
Last Update Posted: July 18, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by David Wang, Dallas VA Medical Center:
esophageal neoplasms
esophagogastric junction
squamous cell carcinoma
Additional relevant MeSH terms:
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Carcinoma, Squamous Cell
Esophageal Neoplasms
Esophageal Squamous Cell Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Squamous Cell
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP3A Inhibitors