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出境医 / 临床实验 / Evaluating the Effect of Itraconazole on Pathologic Complete Response Rates in Esophageal Cancer

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

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.

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.
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 78 participants
Allocation: N/A
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
Arms and Interventions
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.
Outcome Measures
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.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations

Contacts
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Contact: David Wang, MD, PhD 214-857-0737 davidh.wang@va.gov
Contact: Thai Pham, MD 214-857-1800 thai.pham2@va.gov

Locations
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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    jessica.vallejo@va.gov   
Sponsors and Collaborators
Dallas VA Medical Center
Investigators
Layout table for investigator information
Principal Investigator: David Wang, MD, PhD North Texas Veterans Healthcare System
Tracking Information
First Submitted Date  ICMJE July 10, 2019
First Posted Date  ICMJE July 15, 2019
Last Update Posted Date July 21, 2020
Actual Study Start Date  ICMJE June 24, 2019
Estimated Primary Completion Date June 24, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 10, 2019) 		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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 10, 2019)
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Evaluating the Effect of Itraconazole on Pathologic Complete Response Rates in Esophageal Cancer
Official Title  ICMJE 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
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Esophagus Adenocarcinoma
  • Esophagus Squamous Cell Carcinoma
  • Gastroesophageal Junction Adenocarcinoma
Intervention  ICMJE Drug: Itraconazole
Oral administration of itraconazole twice daily from completion of neoadjuvant chemoradiation until esophagectomy.
Study Arms  ICMJE Experimental: Itraconazole
Itraconazole capsule 300mg twice daily for 6-8 weeks following chemoradation.
Intervention: Drug: Itraconazole
Publications *
  • 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.
  • 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 10, 2019) 		78
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 29, 2022
Estimated Primary Completion Date June 24, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: David Wang, MD, PhD 214-857-0737 davidh.wang@va.gov
Contact: Thai Pham, MD 214-857-1800 thai.pham2@va.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04018872
Other Study ID Numbers  ICMJE 19-017
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE Not Provided
Responsible Party David Wang, Dallas VA Medical Center
Study Sponsor  ICMJE Dallas VA Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: David Wang, MD, PhD North Texas Veterans Healthcare System
PRS Account Dallas VA Medical Center
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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