- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04018872
Evaluating the Effect of Itraconazole on Pathologic Complete Response Rates in Esophageal Cancer
November 2, 2021 updated by: David Wang, Dallas VA Medical Center
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
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.
Study Overview
Status
Recruiting
Conditions
Intervention / Treatment
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.
Study Type
Interventional
Enrollment (Anticipated)
78
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Contact
- Name: David Wang, MD, PhD
- Phone Number: 214-857-0737
- Email: davidh.wang@va.gov
Study Contact Backup
- Name: Thai Pham, MD
- Phone Number: 214-857-1800
- Email: thai.pham2@va.gov
Study Locations
-
-
Texas
-
Dallas, Texas, United States, 75216
- Recruiting
- Dallas VA Medical Center
-
Contact:
- Jessica Vallejo, BSA
-
Contact:
- Phone Number: 214-857-4237
- Email: jessica.vallejo@va.gov
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
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
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Itraconazole
Itraconazole capsule 300mg twice daily for 6-8 weeks following chemoradation.
|
Oral administration of itraconazole twice daily from completion of neoadjuvant chemoradiation until esophagectomy.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
3-4 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
3-4 months
|
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.
|
3-4 months
|
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.
|
1 month.
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Investigators
- Principal Investigator: David Wang, MD, PhD, North Texas Veterans Healthcare System
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- 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.
- 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.
- 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.
- 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.
- 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.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
June 24, 2019
Primary Completion (Anticipated)
June 24, 2026
Study Completion (Anticipated)
September 29, 2026
Study Registration Dates
First Submitted
July 10, 2019
First Submitted That Met QC Criteria
July 10, 2019
First Posted (Actual)
July 15, 2019
Study Record Updates
Last Update Posted (Actual)
November 4, 2021
Last Update Submitted That Met QC Criteria
November 2, 2021
Last Verified
November 1, 2021
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Digestive System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms by Site
- Carcinoma
- Neoplasms, Glandular and Epithelial
- Gastrointestinal Neoplasms
- Digestive System Neoplasms
- Gastrointestinal Diseases
- Head and Neck Neoplasms
- Esophageal Diseases
- Neoplasms, Squamous Cell
- Adenocarcinoma
- Carcinoma, Squamous Cell
- Esophageal Neoplasms
- Esophageal Squamous Cell Carcinoma
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Enzyme Inhibitors
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 Enzyme Inhibitors
- Hormone Antagonists
- Antifungal Agents
- Steroid Synthesis Inhibitors
- 14-alpha Demethylase Inhibitors
- Itraconazole
Other Study ID Numbers
- 19-017
Drug and device information, study documents
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
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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