Evaluating the Effect of Itraconazole on Pathologic Complete Response Rates in Esophageal Cancer
Primary Purpose
Esophagus Adenocarcinoma, Esophagus Squamous Cell Carcinoma, Gastroesophageal Junction Adenocarcinoma
Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Itraconazole
Sponsored by
About this trial
This is an interventional treatment trial for Esophagus Adenocarcinoma focused on measuring itraconazole, esophageal neoplasms, esophagus, esophagogastric junction, adenocarcinoma, squamous cell carcinoma
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
Sites / Locations
- Dallas VA Medical CenterRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Itraconazole
Arm Description
Itraconazole capsule 300mg twice daily for 6-8 weeks following chemoradation.
Outcomes
Primary Outcome Measures
Percentage of pathological complete response with itraconazole
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
Comparison of hedgehog biomarkers before and after intervention
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.
Comparison of phosphorylated VEGFR2 and AKT before and after intervention
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.
Levels of itraconazole and metabolites in esophageal tissue
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.
Full Information
NCT ID
NCT04018872
First Posted
July 10, 2019
Last Updated
November 2, 2021
Sponsor
Dallas VA Medical Center
1. Study Identification
Unique Protocol Identification Number
NCT04018872
Brief Title
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
2. Study Status
Record Verification Date
November 2021
Overall Recruitment Status
Recruiting
Study Start Date
June 24, 2019 (Actual)
Primary Completion Date
June 24, 2026 (Anticipated)
Study Completion Date
September 29, 2026 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Dallas VA Medical Center
4. Oversight
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
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Esophagus Adenocarcinoma, Esophagus Squamous Cell Carcinoma, Gastroesophageal Junction Adenocarcinoma
Keywords
itraconazole, esophageal neoplasms, esophagus, esophagogastric junction, adenocarcinoma, squamous cell carcinoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
78 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Itraconazole
Arm Type
Experimental
Arm Description
Itraconazole capsule 300mg twice daily for 6-8 weeks following chemoradation.
Intervention Type
Drug
Intervention Name(s)
Itraconazole
Intervention Description
Oral administration of itraconazole twice daily from completion of neoadjuvant chemoradiation until esophagectomy.
Primary Outcome Measure Information:
Title
Percentage of pathological complete response with itraconazole
Description
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.
Time Frame
3-4 months
Secondary Outcome Measure Information:
Title
Comparison of hedgehog biomarkers before and after intervention
Description
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.
Time Frame
3-4 months
Title
Comparison of phosphorylated VEGFR2 and AKT before and after intervention
Description
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.
Time Frame
3-4 months
Title
Levels of itraconazole and metabolites in esophageal tissue
Description
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.
Time Frame
1 month.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
David Wang, MD, PhD
Phone
214-857-0737
Email
davidh.wang@va.gov
First Name & Middle Initial & Last Name or Official Title & Degree
Thai Pham, MD
Phone
214-857-1800
Email
thai.pham2@va.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Wang, MD, PhD
Organizational Affiliation
North Texas Veterans Healthcare System
Official's Role
Principal Investigator
Facility Information:
Facility Name
Dallas VA Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75216
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jessica Vallejo, BSA
Phone
214-857-4237
Email
jessica.vallejo@va.gov
12. IPD Sharing Statement
Citations:
PubMed Identifier
24493717
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.
Results Reference
background
PubMed Identifier
23340005
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.
Results Reference
background
PubMed Identifier
22025615
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.
Results Reference
background
PubMed Identifier
20385363
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.
Results Reference
background
PubMed Identifier
29592879
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.
Results Reference
background
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Evaluating the Effect of Itraconazole on Pathologic Complete Response Rates in Esophageal Cancer
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